Chk1 Promotes Non-homologous End Joining in G1 Through Direct Phosphorylation of ASF1A

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2021 Jan 27

PMID 33503415

Citations 8

Authors

Kyung Yong Lee

Anindya Dutta

Affiliations

Soon will be listed here.

Abstract

The cell-cycle phase is a major determinant of repair pathway choice at DNA double strand breaks, non-homologous end joining (NHEJ), or homologous recombination (HR). Chk1 responds to genotoxic stress in S/G2 phase, but here, we report a role of Chk1 in directly promoting NHEJ repair in G1 phase. ASF1A is a histone chaperone, but it promotes NHEJ through a pathway independent of its histone-chaperone activity. Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks. Chk1 deficiency suppresses all steps downstream of MDC1 following a DNA break in G1, namely histone ubiquitination, 53BP1 localization to the DNA break, and NHEJ. Thus, ASF1A phosphorylation by Chk1 is essential for DNA break repair by NHEJ in G1.

Citing Articles

Tousled-like kinase loss confers PARP inhibitor resistance in BRCA1-mutated cancers by impeding non-homologous end joining repair.

Kim M, Kim B, Jeon J, Lee J, Jang H, Baek M Mol Med. 2025; 31(1):18.

PMID: 39844055 PMC: 11753094. DOI: 10.1186/s10020-025-01066-z.

Identification of mitochondrial ATP synthase as the cellular target of Ru-polypyridyl--carboline complexes by affinity-based protein profiling.

Wang W, Ling Y, Shi Y, Wu X, Su X, Li Z Natl Sci Rev. 2024; 11(8):nwae234.

PMID: 39114378 PMC: 11304990. DOI: 10.1093/nsr/nwae234.

The TLK-ASF1 histone chaperone pathway plays a critical role in IL-1β-mediated AML progression.

Lin H, Mohammadhosseini M, McClatchy J, Villamor-Paya M, Jeng S, Bottomly D Blood. 2024; 143(26):2749-2762.

PMID: 38498025 PMC: 11340594. DOI: 10.1182/blood.2023022079.

Stixova L, Tichy V, Bartova E Heliyon. 2024; 10(4):e25599.

PMID: 38370261 PMC: 10869776. DOI: 10.1016/j.heliyon.2024.e25599.

Exploiting the DNA Damage Response for Prostate Cancer Therapy.

Stracker T, Osagie O, Escorcia F, Citrin D Cancers (Basel). 2024; 16(1).

PMID: 38201511 PMC: 10777950. DOI: 10.3390/cancers16010083.

References

Das C, Lucia M, Hansen K, Tyler J . CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature. 2009; 459(7243):113-7. PMC: 2756583. DOI: 10.1038/nature07861. View

Liang X, Yuan X, Yu J, Wu Y, Li K, Sun C . Histone Chaperone ASF1A Predicts Poor Outcomes for Patients With Gastrointestinal Cancer and Drives Cancer Progression by Stimulating Transcription of β-Catenin Target Genes. EBioMedicine. 2017; 21:104-116. PMC: 5514402. DOI: 10.1016/j.ebiom.2017.06.007. View

Feng L, Li N, Li Y, Wang J, Gao M, Wang W . Cell cycle-dependent inhibition of 53BP1 signaling by BRCA1. Cell Discov. 2016; 1:15019. PMC: 4860855. DOI: 10.1038/celldisc.2015.19. View

Krause D, Jonnalagadda J, Gatei M, Sillje H, Zhou B, Nigg E . Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1. Oncogene. 2003; 22(38):5927-37. DOI: 10.1038/sj.onc.1206691. View

Kolas N, Chapman J, Nakada S, Ylanko J, Chahwan R, Sweeney F . Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science. 2007; 318(5856):1637-40. PMC: 2430610. DOI: 10.1126/science.1150034. View

Wu L, Luo K, Lou Z, Chen J . MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks. Proc Natl Acad Sci U S A. 2008; 105(32):11200-5. PMC: 2516250. DOI: 10.1073/pnas.0802885105. View

Golding S, Morgan R, Adams B, Hawkins A, Povirk L, Valerie K . Pro-survival AKT and ERK signaling from EGFR and mutant EGFRvIII enhances DNA double-strand break repair in human glioma cells. Cancer Biol Ther. 2009; 8(8):730-8. PMC: 2863288. DOI: 10.4161/cbt.8.8.7927. View

Lou Z, Minter-Dykhouse K, Franco S, Gostissa M, Rivera M, Celeste A . MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol Cell. 2006; 21(2):187-200. DOI: 10.1016/j.molcel.2005.11.025. View

Sillje H, Nigg E . Identification of human Asf1 chromatin assembly factors as substrates of Tousled-like kinases. Curr Biol. 2001; 11(13):1068-73. DOI: 10.1016/s0960-9822(01)00298-6. View

10.

Ismail I, Gagne J, Genois M, Strickfaden H, McDonald D, Xu Z . The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice. Nat Cell Biol. 2015; 17(11):1446-57. DOI: 10.1038/ncb3259. View

11.

Sengupta S, Robles A, Linke S, Sinogeeva N, Zhang R, Pedeux R . Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest. J Cell Biol. 2004; 166(6):801-13. PMC: 2172115. DOI: 10.1083/jcb.200405128. View

12.

Shrivastav M, De Haro L, Nickoloff J . Regulation of DNA double-strand break repair pathway choice. Cell Res. 2007; 18(1):134-47. DOI: 10.1038/cr.2007.111. View

13.

Huang T, Fowler F, Chen C, Shen Z, Sleckman B, Tyler J . The Histone Chaperones ASF1 and CAF-1 Promote MMS22L-TONSL-Mediated Rad51 Loading onto ssDNA during Homologous Recombination in Human Cells. Mol Cell. 2018; 69(5):879-892.e5. PMC: 5843376. DOI: 10.1016/j.molcel.2018.01.031. View

14.

Lee K, Im J, Shibata E, Park J, Handa N, Kowalczykowski S . MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex. Nat Commun. 2015; 6:7744. PMC: 4525285. DOI: 10.1038/ncomms8744. View

15.

Ransburgh D, Chiba N, Ishioka C, Toland A, Parvin J . Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination. Cancer Res. 2010; 70(3):988-95. PMC: 2943742. DOI: 10.1158/0008-5472.CAN-09-2850. View

16.

Wu Y, Li X, Yu J, Bjorkholm M, Xu D . ASF1a inhibition induces p53-dependent growth arrest and senescence of cancer cells. Cell Death Dis. 2019; 10(2):76. PMC: 6349940. DOI: 10.1038/s41419-019-1357-z. View

17.

Iyama T, Wilson 3rd D . DNA repair mechanisms in dividing and non-dividing cells. DNA Repair (Amst). 2013; 12(8):620-36. PMC: 3720834. DOI: 10.1016/j.dnarep.2013.04.015. View

18.

Mao Z, Bozzella M, Seluanov A, Gorbunova V . Comparison of nonhomologous end joining and homologous recombination in human cells. DNA Repair (Amst). 2008; 7(10):1765-71. PMC: 2695993. DOI: 10.1016/j.dnarep.2008.06.018. View

19.

Hromas R, Williamson E, Fnu S, Lee Y, Park S, Beck B . Chk1 phosphorylation of Metnase enhances DNA repair but inhibits replication fork restart. Oncogene. 2012; 31(38):4245-54. PMC: 3963179. DOI: 10.1038/onc.2011.586. View

20.

Brandsma I, Fleuren E, Williamson C, Lord C . Directing the use of DDR kinase inhibitors in cancer treatment. Expert Opin Investig Drugs. 2017; 26(12):1341-1355. PMC: 6157710. DOI: 10.1080/13543784.2017.1389895. View