HMSH5 Regulates NHEJ and Averts Excessive Nucleotide Alterations at Repair Joints

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2022 Apr 23

PMID 35456479

Authors

Aneesa T Al-Soodani

Xiling Wu

Nicole C Kelp

Alexander J Brown

Steven A Roberts

Chengtao Her

Affiliations

Soon will be listed here.

Abstract

Inappropriate repair of DNA double-strand breaks (DSBs) leads to genomic instability, cell death, or malignant transformation. Cells minimize these detrimental effects by selectively activating suitable DSB repair pathways in accordance with their underlying cellular context. Here, we report that hMSH5 down-regulates NHEJ and restricts the extent of DSB end processing before rejoining, thereby reducing "excessive" deletions and insertions at repair joints. RNAi-mediated knockdown of hMSH5 led to large nucleotide deletions and longer insertions at the repair joints, while at the same time reducing the average length of microhomology (MH) at repair joints. Conversely, hMSH5 overexpression reduced end-joining activity and increased RPA foci formation (i.e., more stable ssDNA at DSB ends). Furthermore, silencing of hMSH5 delayed 53BP1 chromatin spreading, leading to increased end resection at DSB ends.

References

Tompkins J, Wu X, Her C . MutS homologue hMSH5: role in cisplatin-induced DNA damage response. Mol Cancer. 2012; 11:10. PMC: 3325843. DOI: 10.1186/1476-4598-11-10. View

Chu Y, Wu X, Xu Y, Her C . MutS homologue hMSH4: interaction with eIF3f and a role in NHEJ-mediated DSB repair. Mol Cancer. 2013; 12:51. PMC: 3689047. DOI: 10.1186/1476-4598-12-51. View

Lee-Theilen M, Matthews A, Kelly D, Zheng S, Chaudhuri J . CtIP promotes microhomology-mediated alternative end joining during class-switch recombination. Nat Struct Mol Biol. 2010; 18(1):75-9. PMC: 3471154. DOI: 10.1038/nsmb.1942. View

Edelmann W, Cohen P, Kneitz B, Winand N, Lia M, HEYER J . Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nat Genet. 1999; 21(1):123-7. DOI: 10.1038/5075. View

Soutoglou E, Dorn J, Sengupta K, Jasin M, Nussenzweig A, Ried T . Positional stability of single double-strand breaks in mammalian cells. Nat Cell Biol. 2007; 9(6):675-82. PMC: 2442898. DOI: 10.1038/ncb1591. View

Helmink B, Tubbs A, Dorsett Y, Bednarski J, Walker L, Feng Z . H2AX prevents CtIP-mediated DNA end resection and aberrant repair in G1-phase lymphocytes. Nature. 2010; 469(7329):245-9. PMC: 3150591. DOI: 10.1038/nature09585. View

de Vries S, Baart E, Dekker M, Siezen A, de Rooij D, de Boer P . Mouse MutS-like protein Msh5 is required for proper chromosome synapsis in male and female meiosis. Genes Dev. 1999; 13(5):523-31. PMC: 316502. DOI: 10.1101/gad.13.5.523. View

Lee T, Yi W, Griswold M, Zhu F, Her C . Formation of hMSH4-hMSH5 heterocomplex is a prerequisite for subsequent GPS2 recruitment. DNA Repair (Amst). 2005; 5(1):32-42. DOI: 10.1016/j.dnarep.2005.07.004. View

Zimmermann M, Lottersberger F, Buonomo S, Sfeir A, de Lange T . 53BP1 regulates DSB repair using Rif1 to control 5' end resection. Science. 2013; 339(6120):700-4. PMC: 3664841. DOI: 10.1126/science.1231573. View

10.

Sekine H, Ferreira R, Pan-Hammarstrom Q, Graham R, Ziemba B, de Vries S . Role for Msh5 in the regulation of Ig class switch recombination. Proc Natl Acad Sci U S A. 2007; 104(17):7193-8. PMC: 1855370. DOI: 10.1073/pnas.0700815104. View

11.

Rodrigue A, Lafrance M, Gauthier M, McDonald D, Hendzel M, West S . Interplay between human DNA repair proteins at a unique double-strand break in vivo. EMBO J. 2006; 25(1):222-31. PMC: 1356357. DOI: 10.1038/sj.emboj.7600914. View

12.

Olive P . Retention of γH2AX foci as an indication of lethal DNA damage. Radiother Oncol. 2011; 101(1):18-23. DOI: 10.1016/j.radonc.2011.05.055. View

13.

Lieber M . The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 2010; 79:181-211. PMC: 3079308. DOI: 10.1146/annurev.biochem.052308.093131. View

14.

Her C, Wu X, Wan W, Doggett N . Identification and characterization of the mouse MutS homolog 5: Msh5. Mamm Genome. 1999; 10(11):1054-61. DOI: 10.1007/s003359901161. View

15.

Her C, Vo A, Wu X . Evidence for a direct association of hMRE11 with the human mismatch repair protein hMLH1. DNA Repair (Amst). 2003; 1(9):719-29. DOI: 10.1016/s1568-7864(02)00079-4. View

16.

Saleh-Gohari N, Helleday T . Conservative homologous recombination preferentially repairs DNA double-strand breaks in the S phase of the cell cycle in human cells. Nucleic Acids Res. 2004; 32(12):3683-8. PMC: 484186. DOI: 10.1093/nar/gkh703. View

17.

Ochs F, Somyajit K, Altmeyer M, Rask M, Lukas J, Lukas C . 53BP1 fosters fidelity of homology-directed DNA repair. Nat Struct Mol Biol. 2016; 23(8):714-21. DOI: 10.1038/nsmb.3251. View

18.

Kent T, Clynes D . Alternative Lengthening of Telomeres: Lessons to Be Learned from Telomeric DNA Double-Strand Break Repair. Genes (Basel). 2021; 12(11). PMC: 8619803. DOI: 10.3390/genes12111734. View

19.

Rothkamm K, Kruger I, Thompson L, Lobrich M . Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol. 2003; 23(16):5706-15. PMC: 166351. DOI: 10.1128/MCB.23.16.5706-5715.2003. View

20.

Yi W, Lee T, Tompkins J, Zhu F, Wu X, Her C . Physical and functional interaction between hMSH5 and c-Abl. Cancer Res. 2006; 66(1):151-8. DOI: 10.1158/0008-5472.CAN-05-3019. View