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Decoding replication stress responses through post-translational modifications

Nature Chemical Biology (2025)Cite this article

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Abstract

DNA replication is a fundamental cellular process that ensures the faithful duplication of the genome during cell division. However, this process is frequently challenged by various intrinsic and extrinsic factors that can impede replication fork progression and jeopardize genomic integrity. To safeguard against these challenges, cells have evolved intricate stress response mechanisms, including replication checkpoint activation, translesion DNA synthesis, repriming and fork reversal, all of which are vital for preserving genomic stability. Central to the orchestration of these pathways are post-translational modifications (PTMs), which dynamically regulate the stability, localization, and activity of key proteins involved in the replication stress responses. In this Review, we summarize the primary mechanisms that orchestrate cellular responses to replication stress and highlight emerging insights into the roles of both histone and nonhistone PTMs in the precise and coordinated regulation of replication fork dynamics under genotoxic conditions.

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Fig. 1: Mechanisms of replication fork protection under replication stress.
Fig. 2: Acetylation regulates replication checkpoint activation.
Fig. 3: PARylation modulates replication stress responses.
Fig. 4: UFMylation in replication stress responses.
Fig. 5: Histone PTMs in replication stress responses.

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References

  1. Zeman, M. K. & Cimprich, K. A. Causes and consequences of replication stress. Nat. Cell Biol. 16, 2–9 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Berti, M., Cortez, D. & Lopes, M. The plasticity of DNA replication forks in response to clinically relevant genotoxic stress. Nat. Rev. Mol. Cell Biol. 21, 633–651 (2020).

    Article  CAS  PubMed  Google Scholar 

  3. Saxena, S. & Zou, L. Hallmarks of DNA replication stress. Mol. Cell 82, 2298–2314 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Neelsen, K. J. & Lopes, M. Replication fork reversal in eukaryotes: from dead end to dynamic response. Nat. Rev. Mol. Cell Biol. 16, 207–220 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. Qiu, S., Jiang, G., Cao, L. & Huang, J. Replication fork reversal and protection. Front. Cell Dev. Biol. 9, 670392 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Marians, K. J. Lesion bypass and the reactivation of stalled replication forks. Annu. Rev. Biochem. 87, 217–238 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Quinet, A., Tirman, S., Cybulla, E., Meroni, A. & Vindigni, A. To skip or not to skip: choosing repriming to tolerate DNA damage. Mol. Cell 81, 649–658 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Saldivar, J. C., Cortez, D. & Cimprich, K. A. The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat. Rev. Mol. Cell Biol. 18, 622–636 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Simoneau, A. & Zou, L. An extending ATR-CHK1 circuitry: the replication stress response and beyond. Curr. Opin. Genet. Dev. 71, 92–98 (2021).

    Article  CAS  PubMed  Google Scholar 

  10. Gaillard, H., García-Muse, T. & Aguilera, A. Replication stress and cancer. Nat. Rev. Cancer 15, 276–289 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Macheret, M. & Halazonetis, T. D. DNA replication stress as a hallmark of cancer. Annu. Rev. Pathol. 10, 425–448 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Lee, J. M., Hammarén, H. M., Savitski, M. M. & Baek, S. H. Control of protein stability by post-translational modifications. Nat. Commun. 14, 201 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dikic, I. & Schulman, B. A. An expanded lexicon for the ubiquitin code. Nat. Rev. Mol. Cell Biol. 24, 273–287 (2023).

    Article  CAS  PubMed  Google Scholar 

  14. Millán-Zambrano, G., Burton, A., Bannister, A. J. & Schneider, R. Histone post-translational modifications—cause and consequence of genome function. Nat. Rev. Genet. 23, 563–580 (2022).

    Article  PubMed  Google Scholar 

  15. Byun, T. S., Pacek, M., Yee, M. C., Walter, J. C. & Cimprich, K. A. Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 19, 1040–1052 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lopes, M., Foiani, M. & Sogo, J. M. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol. Cell 21, 15–27 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Maréchal, A. & Zou, L. RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response. Cell Res. 25, 9–23 (2015).

    Article  PubMed  Google Scholar 

  18. Liu, T. & Huang, J. Replication protein A and more: single-stranded DNA-binding proteins in eukaryotic cells. Acta Biochim. Biophys. Sin. (Shanghai) 48, 665–670 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Zou, L. & Elledge, S. J. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300, 1542–1548 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Ngoi, N. Y. L. et al. Targeting ATR in patients with cancer. Nat. Rev. Clin. Oncol. 21, 278–293 (2024).

    Article  PubMed  Google Scholar 

  21. Kavlashvili, T., Liu, W., Mohamed, T. M., Cortez, D. & Dewar, J. M. Replication fork uncoupling causes nascent strand degradation and fork reversal. Nat. Struct. Mol. Biol. 30, 115–124 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Joseph, S. A. et al. Time for remodeling: SNF2-family DNA translocases in replication fork metabolism and human disease. DNA Repair (Amst.) 95, 102943 (2020).

    Article  CAS  PubMed  Google Scholar 

  23. Tian, T. et al. The ZATT-TOP2A-PICH axis drives extensive replication fork reversal to promote genome stability. Mol. Cell 81, 198–211 (2021).

    Article  CAS  PubMed  Google Scholar 

  24. Ding, L. et al. RNF4 controls the extent of replication fork reversal to preserve genome stability. Nucleic Acids Res. 50, 5672–5687 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu, W. et al. RAD51 bypasses the CMG helicase to promote replication fork reversal. Science 380, 382–387 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bugreev, D. V., Rossi, M. J. & Mazin, A. V. Cooperation of RAD51 and RAD54 in regression of a model replication fork. Nucleic Acids Res. 39, 2153–2164 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Halder, S., Ranjha, L., Taglialatela, A., Ciccia, A. & Cejka, P. Strand annealing and motor driven activities of SMARCAL1 and ZRANB3 are stimulated by RAD51 and the paralog complex. Nucleic Acids Res. 50, 8008–8022 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pasero, P. & Vindigni, A. Nucleases acting at stalled forks: how to reboot the replication program with a few shortcuts. Annu. Rev. Genet. 51, 477–499 (2017).

    Article  CAS  PubMed  Google Scholar 

  29. Bhat, K. P. & Cortez, D. RPA and RAD51: fork reversal, fork protection, and genome stability. Nat. Struct. Mol. Biol. 25, 446–453 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xu, S. et al. Abro1 maintains genome stability and limits replication stress by protecting replication fork stability. Genes Dev. 31, 1469–1482 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Song, L. et al. Dynamic control of RNA-DNA hybrid formation orchestrates DNA2 activation at stalled forks by RNAPII and DDX39A. Mol. Cell 85, 506–522 (2025).

    Article  CAS  PubMed  Google Scholar 

  32. Xu, Z. et al. DDX39A resolves replication fork-associated RNA-DNA hybrids to balance fork protection and cleavage for genomic stability maintenance. Mol. Cell 85, 490–505 (2025).

    Article  CAS  PubMed  Google Scholar 

  33. Berti, M. et al. Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat. Struct. Mol. Biol. 20, 347–354 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Thangavel, S. et al. DNA2 drives processing and restart of reversed replication forks in human cells. J. Cell Biol. 208, 545–562 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xie, H. et al. Synergistic protection of nascent DNA at stalled forks by MSANTD4 and BRCA1/2-RAD51. Nat. Chem. Biol. 21, 1182–1193 (2025).

    Article  CAS  PubMed  Google Scholar 

  36. Bryant, H. E. et al. PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination. EMBO J. 28, 2601–2615 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bianchi, J. et al. PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication. Mol. Cell 52, 566–573 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wan, L. et al. hPrimpol1/CCDC111 is a human DNA primase-polymerase required for the maintenance of genome integrity. EMBO Rep. 14, 1104–1112 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mourón, S. et al. Repriming of DNA synthesis at stalled replication forks by human PrimPol. Nat. Struct. Mol. Biol. 20, 1383–1389 (2013).

    Article  PubMed  Google Scholar 

  40. García-Gómez, S. et al. PrimPol, an archaic primase/polymerase operating in human cells. Mol. Cell 52, 541–553 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tirman, S. et al. Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells. Mol. Cell 81, 4026–4040 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Taglialatela, A. et al. REV1-Polζ maintains the viability of homologous recombination-deficient cancer cells through mutagenic repair of PRIMPOL-dependent ssDNA gaps. Mol. Cell 81, 4008–4025 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mirsanaye, A. S., Typas, D. & Mailand, N. Ubiquitylation at stressed replication forks: mechanisms and functions. Trends Cell Biol. 31, 584–597 (2021).

    Article  CAS  PubMed  Google Scholar 

  44. García-Rodríguez, N., Wong, R. P. & Ulrich, H. D. Functions of ubiquitin and SUMO in DNA replication and replication stress. Front. Genet. 7, 87 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Chen, Y. & Yuan, J. The post translational modification of key regulators of ATR signaling in DNA replication. Genome Instab. Dis. 2, 92–101 (2021).

    Article  CAS  Google Scholar 

  46. Narita, T., Weinert, B. T. & Choudhary, C. Functions and mechanisms of non-histone protein acetylation. Nat. Rev. Mol. Cell Biol. 20, 156–174 (2019).

    Article  CAS  PubMed  Google Scholar 

  47. Shvedunova, M. & Akhtar, A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat. Rev. Mol. Cell Biol. 23, 329–349 (2022).

    Article  CAS  PubMed  Google Scholar 

  48. Zhang, H. et al. ATRIP deacetylation by SIRT2 drives ATR checkpoint activation by promoting binding to RPA-ssDNA. Cell Rep. 14, 1435–1447 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu, T. et al. A divergent role of the SIRT1-TopBP1 axis in regulating metabolic checkpoint and DNA damage checkpoint. Mol. Cell 56, 681–695 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Matheson, C. J., Backos, D. S. & Reigan, P. Targeting WEE1 kinase in cancer. Trends Pharmacol. Sci. 37, 872–881 (2016).

    Article  CAS  PubMed  Google Scholar 

  51. Zhu, X. et al. SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition. Nat. Chem. Biol. 19, 585–595 (2023).

    Article  CAS  PubMed  Google Scholar 

  52. Yuan, J., Luo, K., Liu, T. & Lou, Z. Regulation of SIRT1 activity by genotoxic stress. Genes Dev. 26, 791–796 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zannini, L., Buscemi, G., Kim, J. E., Fontanella, E. & Delia, D. DBC1 phosphorylation by ATM/ATR inhibits SIRT1 deacetylase in response to DNA damage. J. Mol. Cell. Biol. 4, 294–303 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Lee, S. Y., Kim, J. J. & Miller, K. M. Bromodomain proteins: protectors against endogenous DNA damage and facilitators of genome integrity. Exp. Mol. Med. 53, 1268–1277 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang, J. et al. BRD4 facilitates replication stress-induced DNA damage response. Oncogene 37, 3763–3777 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Suskiewicz, M. J., Prokhorova, E., Rack, J. G. M. & Ahel, I. ADP-ribosylation from molecular mechanisms to therapeutic implications. Cell 186, 4475–4495 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yu, L., Liu, X. & Yu, X. ADP-ribosylhydrolases: from DNA damage repair to COVID-19. J. Zhejiang Univ. Sci. B 22, 21–30 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Huang, D. & Kraus, W. L. The expanding universe of PARP1-mediated molecular and therapeutic mechanisms. Mol. Cell 82, 2315–2334 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ray Chaudhuri, A. & Nussenzweig, A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat. Rev. Mol. Cell Biol. 18, 610–621 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Azarm, K. & Smith, S. Nuclear PARPs and genome integrity. Genes Dev. 34, 285–301 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hanzlikova, H. et al. The importance of poly(ADP-ribose) polymerase as a sensor of unligated Okazaki fragments during DNA replication. Mol. Cell 71, 319–331 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vaitsiankova, A. et al. PARP inhibition impedes the maturation of nascent DNA strands during DNA replication. Nat. Struct. Mol. Biol. 29, 329–338 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang, Y. G., Cortes, U., Patnaik, S., Jasin, M. & Wang, Z. Q. Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks. Oncogene 23, 3872–3882 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Ray Chaudhuri, A. et al. Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat. Struct. Mol. Biol. 19, 417–423 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Min, W. et al. Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation. Nat. Commun. 4, 2993 (2013).

    Article  PubMed  Google Scholar 

  66. Duursma, A. M., Driscoll, R., Elias, J. E. & Cimprich, K. A. A role for the MRN complex in ATR activation via TOPBP1 recruitment. Mol. Cell 50, 116–122 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee, J. & Dunphy, W. G. The Mre11–Rad50–Nbs1 (MRN) complex has a specific role in the activation of Chk1 in response to stalled replication forks. Mol. Biol. Cell 24, 1343–1353 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ho, Y. C. et al. PARP1 recruits DNA translocases to restrain DNA replication and facilitate DNA repair. PLoS Genet. 18, e1010545 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Margalef, P. et al. Stabilization of reversed replication forks by telomerase drives telomere catastrophe. Cell 172, 439–453 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ray Chaudhuri, A., Ahuja, A. K., Herrador, R. & Lopes, M. Poly(ADP-ribosyl) glycohydrolase prevents the accumulation of unusual replication structures during unperturbed S phase. Mol. Cell. Biol. 35, 856–865 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Wu, C. K. et al. APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance. Nucleic Acids Res. 52, 5676–5697 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hammel, M. et al. An intrinsically disordered APLF links Ku, DNA-PKcs, and XRCC4-DNA ligase IV in an extended flexible non-homologous end joining complex. J. Biol. Chem. 291, 26987–27006 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Patel, J. A. & Kim, H. The TIMELESS effort for timely DNA replication and protection. Cell. Mol. Life Sci. 80, 84 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Rageul, J. et al. Poly(ADP-ribosyl)ation of TIMELESS limits DNA replication stress and promotes stalled fork protection. Cell Rep. 43, 113845 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Haince, J. F. et al. PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J. Biol. Chem. 283, 1197–1208 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Ding, X. et al. Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies. Nat. Commun. 7, 12425 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Petermann, E., Orta, M. L., Issaeva, N., Schultz, N. & Helleday, T. Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol. Cell 37, 492–502 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang, F., Shi, J., Chen, S. H., Bian, C. & Yu, X. The PIN domain of EXO1 recognizes poly(ADP-ribose) in DNA damage response. Nucleic Acids Res. 43, 10782–10794 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Cheruiyot, A. et al. Poly(ADP-ribose)-binding promotes Exo1 damage recruitment and suppresses its nuclease activities. DNA Repair (Amst.) 35, 106–115 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Ray Chaudhuri, A. et al. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535, 382–387 (2016).

    Article  PubMed  Google Scholar 

  81. Dhoonmoon, A., Nicolae, C. M. & Moldovan, G. L. The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1. Nat. Commun. 13, 5063 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Paull, T. T. 20 years of Mre11 biology: no end in sight. Mol. Cell 71, 419–427 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Qiu, S. & Huang, J. MRN complex is an essential effector of DNA damage repair. J. Zhejiang Univ. Sci. B 22, 31–37 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Carter-O’Connell, I. et al. Combining chemical genetics with proximity-dependent labeling reveals cellular targets of Poly(ADP-ribose) polymerase 14 (PARP14). ACS Chem. Biol. 13, 2841–2848 (2018).

    Article  PubMed  Google Scholar 

  85. Kliza, K. W. et al. Reading ADP-ribosylation signaling using chemical biology and interaction proteomics. Mol. Cell 81, 4552–4567 (2021).

    Article  CAS  PubMed  Google Scholar 

  86. Gu Kang, B. et al. Proteome-wide microarray-based screening of PAR-binding proteins. Nucleic Acids Res. 53, gkaf300 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Zhou, X. et al. UFMylation: a ubiquitin-like modification. Trends Biochem. Sci. 49, 52–67 (2024).

    Article  CAS  PubMed  Google Scholar 

  88. Komatsu, M., Inada, T. & Noda, N. N. The UFM1 system: working principles, cellular functions, and pathophysiology. Mol. Cell 84, 156–169 (2024).

    Article  CAS  PubMed  Google Scholar 

  89. Gong, Y. et al. PARP1 UFMylation ensures the stability of stalled replication forks. Proc. Natl Acad. Sci. USA 121, e2322520121 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Schlacher, K. et al. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145, 529–542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Schlacher, K., Wu, H. & Jasin, M. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22, 106–116 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liao, H., Ji, F., Helleday, T. & Ying, S. Mechanisms for stalled replication fork stabilization: new targets for synthetic lethality strategies in cancer treatments. EMBO Rep. 19, e46263 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Cybulla, E. & Vindigni, A. Leveraging the replication stress response to optimize cancer therapy. Nat. Rev. Cancer 23, 6–24 (2023).

    Article  CAS  PubMed  Google Scholar 

  94. Cho, Y. W. et al. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J. Biol. Chem. 282, 20395–20406 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Tian, T. et al. UFL1 triggers replication fork degradation by MRE11 in BRCA1/2-deficient cells. Nat. Chem. Biol. 20, 1650–1661 (2024).

    Article  CAS  PubMed  Google Scholar 

  96. Tan, Q. & Xu, X. PTIP UFMylation promotes replication fork degradation in BRCA1-deficient cells. J. Biol. Chem. 300, 107312 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wang, Z. et al. MRE11 UFMylation promotes ATM activation. Nucleic Acids Res. 47, 4124–4135 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Qin, B. et al. STK38 promotes ATM activation by acting as a reader of histone H4 UFMylation. Sci. Adv. 6, eaax8214 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Patel, S. R., Kim, D., Levitan, I. & Dressler, G. R. The BRCT-domain containing protein PTIP links PAX2 to a histone H3, lysine 4 methyltransferase complex. Dev. Cell 13, 580–592 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Starnes, L. M. et al. A PTIP–PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex. Genes Dev. 30, 149–163 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tan, Q. & Xu, X. MUS81 UFMylation at K400 promotes cell survival in response to camptothecin-induced replication stress. Genome Instab. Dis. 5, 154–163 (2024).

    Article  CAS  Google Scholar 

  102. Hsu, C. L., Chong, S. Y., Lin, C. Y. & Kao, C. F. Histone dynamics during DNA replication stress. J. Biomed. Sci. 28, 48 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Greer, E. L. & Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13, 343–357 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhu, Q. et al. SETD2-mediated H3K14 trimethylation promotes ATR activation and stalled replication fork restart in response to DNA replication stress. Proc. Natl Acad. Sci. USA 118, e2011278118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. McDaniel, S. L. & Strahl, B. D. Shaping the cellular landscape with Set2/SETD2 methylation. Cell. Mol. Life Sci. 74, 3317–3334 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Liu, H. et al. Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint. Nature 467, 343–346 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Higgs, M. R. et al. Histone methylation by SETD1A protects nascent DNA through the nucleosome chaperone activity of FANCD2. Mol. Cell 71, 25–41 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Gaggioli, V. et al. Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability. Nat. Cell Biol. 25, 1017–1032 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wang, L. et al. Histone modifications regulate chromatin compartmentalization by contributing to a phase separation mechanism. Mol. Cell 76, 646–659 (2019).

    Article  CAS  PubMed  Google Scholar 

  110. Li, X., Liu, C., Lei, Z., Chen, H. & Wang, L. Phase-separated chromatin compartments: orchestrating gene expression through condensation. Cell Insight 3, 100213 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Lee, J. E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Muñoz, I. M. & Rouse, J. Control of histone methylation and genome stability by PTIP. EMBO Rep. 10, 239–245 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Rondinelli, B. et al. EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nat. Cell Biol. 19, 1371–1378 (2017).

    Article  CAS  PubMed  Google Scholar 

  114. Przetocka, S. et al. CtIP-mediated fork protection synergizes with BRCA1 to suppress genomic instability upon DNA replication stress. Mol. Cell 72, 568–582 (2018).

    Article  CAS  PubMed  Google Scholar 

  115. Wang, M. et al. Crucial roles of the BRCA1–BARD1 E3 ubiquitin ligase activity in homology-directed DNA repair. Mol. Cell 83, 3679–3691 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Jiang, L., Huang, L. & Jiang, W. H3K27me3-mediated epigenetic regulation in pluripotency maintenance and lineage differentiation. Cell Insight 3, 100180 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Lee, M. G. et al. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318, 447–450 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Wu, J. et al. KDM6A-SND1 interaction maintains genomic stability by protecting the nascent DNA and contributes to cancer chemoresistance. Nucleic Acids Res. 52, 7665–7686 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kim, J. J. et al. PCAF-mediated histone acetylation promotes replication fork degradation by MRE11 and EXO1 in BRCA-deficient cells. Mol. Cell 80, 327–344 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Taglialatela, A. et al. Restoration of replication fork stability in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-family fork remodelers. Mol. Cell 68, 414–430 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kolinjivadi, A. M. et al. SMARCAL1-mediated fork reversal triggers Mre11-dependent degradation of nascent DNA in the absence of Brca2 and stable Rad51 nucleofilaments. Mol. Cell 67, 867–881 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Muñoz, S. et al. SIN3A histone deacetylase action counteracts MUS81 to promote stalled fork stability. Cell Rep. 43, 113778 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Andronikou, C. & Rottenberg, S. Studying PAR-dependent chromatin remodeling to tackle PARPi resistance. Trends Mol. Med. 27, 630–642 (2021).

    Article  CAS  PubMed  Google Scholar 

  124. Zentout, S. et al. Histone ADP-ribosylation promotes resistance to PARP inhibitors by facilitating PARP1 release from DNA lesions. Proc. Natl Acad. Sci. USA 121, e2322689121 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Da Costa, A., Chowdhury, D., Shapiro, G. I., D’Andrea, A. D. & Konstantinopoulos, P. A. Targeting replication stress in cancer therapy. Nat. Rev. Drug Discov. 22, 38–58 (2023).

    Article  PubMed  Google Scholar 

  126. Pfister, S. X. et al. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28, 557–568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Pillay, N. et al. DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors. Cancer Cell 35, 519–533 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Baillie, K. E. & Stirling, P. C. Beyond kinases: targeting replication stress proteins in cancer therapy. Trends Cancer 7, 430–446 (2021).

    Article  CAS  PubMed  Google Scholar 

  129. Wu, Z., Liu, Y., Zhang, M. & Wang, D. Emerging posttranslational modifications and their roles in DNA damage response. Genome Instab. Dis. 5, 1–16 (2024).

    Article  CAS  Google Scholar 

  130. Dai, E., Wang, W., Li, Y., Ye, D. & Li, Y. Lactate and lactylation: behind the development of tumors. Cancer Lett. 591, 216896 (2024).

    Article  CAS  PubMed  Google Scholar 

  131. Bergers, G. & Fendt, S. M. The metabolism of cancer cells during metastasis. Nat. Rev. Cancer 21, 162–180 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhang, Y. et al. The function and mechanism of lactate and lactylation in tumor metabolism and microenvironment. Genes Dis. 10, 2029–2037 (2023).

    Article  CAS  PubMed  Google Scholar 

  133. Zecha, J. et al. Decrypting drug actions and protein modifications by dose- and time-resolved proteomics. Science 380, 93–101 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rosenberger, F. A. et al. Spatial single-cell mass spectrometry defines zonation of the hepatocyte proteome. Nat. Methods 20, 1530–1536 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhai, Y. et al. Spatiotemporal-resolved protein networks profiling with photoactivation dependent proximity labeling. Nat. Commun. 13, 4906 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Ctortecka, C. et al. Automated single-cell proteomics providing sufficient proteome depth to study complex biology beyond cell type classifications. Nat. Commun. 15, 5707 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Muneer, G. et al. Mapping nanoscale-to-single-cell phosphoproteomic landscape by Chip-DIA. Adv. Sci. (Weinh.) 12, e2402421 (2025).

    PubMed  Google Scholar 

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Acknowledgements

We apologize to colleagues whose work could not be cited due to space constraints. We thank all members of the Liu and Huang laboratories for their valuable discussions. This work was supported by the National Key Research and Development Program of China (2022YFA1302800 to J.H., 2021YFA1101000 to T.L. and 2023YFC2509200 to M.J.W.), the Central guidance for local scientific and technological development funding project (2025ZY01106 to T.L.), the National Natural Science Foundation of China (32525025 to T.L., U24A20717 to J.H., and 32170730 to J.H.H.) and the Natural Science Foundation of Zhejiang Province (LZ24C070002 to J.H. and LR24H140001 to M.J.W.). Figures were created with BioRender.com.

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Authors and Affiliations

  1. Zhejiang Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Jinhua Han, Ting Liu & Jun Huang

  2. Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Zhejiang Key Laboratory of Oral Biomedical, Hangzhou, China

    Mengjie Wu

  3. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China

    Ting Liu

  4. Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China

    Jun Huang

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  1. Jinhua Han
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  2. Mengjie Wu
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  4. Jun Huang
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Contributions

T.L. and J.H. conceived and supervised the project. J.H.H., J.H. and T.L. wrote the manuscript. J.H.H. and M.J.W. prepared the figures and tables. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Ting Liu or Jun Huang.

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Han, J., Wu, M., Liu, T. et al. Decoding replication stress responses through post-translational modifications. Nat Chem Biol (2025). https://doi.org/10.1038/s41589-025-02023-x

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