53BP1-the 'Pandora's Box' of Genome Integrity

Overview

Journal DNA Repair (Amst)

Publisher Elsevier

Specialties Biochemistry
Molecular Biology

Date 2024 Oct 30

PMID 39476547

Authors

Susan Kilgas

Michelle L Swift

Dipanjan Chowdhury

Affiliations

Soon will be listed here.

Abstract

53BP1 has several functions in the maintenance of genome integrity. It functions as a key mediator involved in double-strand break (DSB) repair, which functions to maintain a balance in the repair pathway choices and in preserving genomic stability. While its DSB repair functions are relatively well-characterized, its role in DNA replication and replication fork protection is less understood. In response to replication stress, 53BP1 contributes to fork protection by regulating fork reversal and restart. It helps maintain replication fork stability and speed, with 53BP1 loss leading to defective fork progression and increased sensitivity to replication stress agents. However, 53BP1's precise role in fork protection remains debated, as some studies have not observed protective effects. Therefore, it is critical to determine the role of 53BP1 in replication to better understand when it promotes replication fork protection, and the underlying mechanisms involved. Moreover, 53BP1's function in replication stress extends beyond its activity at active replication forks; it also forms specialized nuclear bodies (NBs) which protect stretches of under-replicated DNA (UR-DNA) transmitted from a previous cell cycle to daughter cells through mitosis. The mechanism of 53BP1 NBs in the coordination of replication and repair events at UR-DNA loci is not fully understood and warrants further investigation. The present review article focuses on elucidating 53BP1's functions in replication stress (RS), its role in replication fork protection, and the significance of 53BP1 NBs in this context to provide a more comprehensive understanding of its less well-established role in DNA replication.

References

Waga S, Stillman B . The DNA replication fork in eukaryotic cells. Annu Rev Biochem. 1998; 67:721-51. DOI: 10.1146/annurev.biochem.67.1.721. View

Schmidt L, Wiedner M, Velimezi G, Prochazkova J, Owusu M, Bauer S . ATMIN is required for the ATM-mediated signaling and recruitment of 53BP1 to DNA damage sites upon replication stress. DNA Repair (Amst). 2014; 24:122-130. PMC: 4251980. DOI: 10.1016/j.dnarep.2014.09.001. View

Mao Y, Zhang B, Spector D . Biogenesis and function of nuclear bodies. Trends Genet. 2011; 27(8):295-306. PMC: 3144265. DOI: 10.1016/j.tig.2011.05.006. View

Xu Y, Ning S, Wei Z, Xu R, Xu X, Xing M . 53BP1 and BRCA1 control pathway choice for stalled replication restart. Elife. 2017; 6. PMC: 5683755. DOI: 10.7554/eLife.30523. View

Sandell L, Zakian V . Loss of a yeast telomere: arrest, recovery, and chromosome loss. Cell. 1993; 75(4):729-39. DOI: 10.1016/0092-8674(93)90493-a. View

Harrigan J, Belotserkovskaya R, Coates J, Dimitrova D, Polo S, Bradshaw C . Replication stress induces 53BP1-containing OPT domains in G1 cells. J Cell Biol. 2011; 193(1):97-108. PMC: 3082192. DOI: 10.1083/jcb.201011083. View

Lo C, van Toorn M, Gaggioli V, Paes Dias M, Zhu Y, Manolika E . SMARCAD1-mediated active replication fork stability maintains genome integrity. Sci Adv. 2021; 7(19). PMC: 8099181. DOI: 10.1126/sciadv.abe7804. View

Baumann C, Korner R, Hofmann K, Nigg E . PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell. 2007; 128(1):101-14. DOI: 10.1016/j.cell.2006.11.041. View

Tripathi V, Nagarjuna T, Sengupta S . BLM helicase-dependent and -independent roles of 53BP1 during replication stress-mediated homologous recombination. J Cell Biol. 2007; 178(1):9-14. PMC: 2064412. DOI: 10.1083/jcb.200610051. View

10.

Joo W, Jeffrey P, Cantor S, Finnin M, Livingston D, Pavletich N . Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure. Genes Dev. 2002; 16(5):583-93. PMC: 155350. DOI: 10.1101/gad.959202. View

11.

Ray Chaudhuri A, Callen E, Ding X, Gogola E, Duarte A, Lee J . Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature. 2016; 535(7612):382-7. PMC: 4959813. DOI: 10.1038/nature18325. View

12.

Pavani R, Tripathi V, Vrtis K, Zong D, Chari R, Callen E . Structure and repair of replication-coupled DNA breaks. Science. 2024; 385(6710):eado3867. PMC: 11620331. DOI: 10.1126/science.ado3867. View

13.

Trendel J, Schwarzl T, Horos R, Prakash A, Bateman A, Hentze M . The Human RNA-Binding Proteome and Its Dynamics during Translational Arrest. Cell. 2018; 176(1-2):391-403.e19. DOI: 10.1016/j.cell.2018.11.004. View

14.

Lukas C, Savic V, Bekker-Jensen S, Doil C, Neumann B, Pedersen R . 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress. Nat Cell Biol. 2011; 13(3):243-53. DOI: 10.1038/ncb2201. View

15.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

16.

Bhowmick R, Hickson I, Liu Y . Completing genome replication outside of S phase. Mol Cell. 2023; 83(20):3596-3607. DOI: 10.1016/j.molcel.2023.08.023. View

17.

Spies J, Lukas C, Somyajit K, Rask M, Lukas J, Neelsen K . 53BP1 nuclear bodies enforce replication timing at under-replicated DNA to limit heritable DNA damage. Nat Cell Biol. 2019; 21(4):487-497. DOI: 10.1038/s41556-019-0293-6. View

18.

Cuella-Martin R, Oliveira C, Lockstone H, Snellenberg S, Grolmusova N, Chapman J . 53BP1 Integrates DNA Repair and p53-Dependent Cell Fate Decisions via Distinct Mechanisms. Mol Cell. 2016; 64(1):51-64. PMC: 5065530. DOI: 10.1016/j.molcel.2016.08.002. View

19.

Bertolin A, Hoffmann J, Gottifredi V . Under-Replicated DNA: The Byproduct of Large Genomes?. Cancers (Basel). 2020; 12(10). PMC: 7601121. DOI: 10.3390/cancers12102764. View

20.

Fradet-Turcotte A, Canny M, Escribano-Diaz C, Orthwein A, Leung C, Huang H . 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature. 2013; 499(7456):50-4. PMC: 3955401. DOI: 10.1038/nature12318. View