MCM8 Interacts with DDX5 to Promote R-loop Resolution

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2024 Jun 10

PMID 38858601

Authors

Canxin Wen

Lili Cao

Shuhan Wang

Weiwei Xu

Yongze Yu

Simin Zhao

Fan Yang

Zi-Jiang Chen

Shidou Zhao

Yajuan Yang

Yingying Qin

Affiliations

Soon will be listed here.

Abstract

MCM8 has emerged as a core gene in reproductive aging and is crucial for meiotic homologous recombination repair. It also safeguards genome stability by coordinating the replication stress response during mitosis, but its function in mitotic germ cells remains elusive. Here we found that disabling MCM8 in mice resulted in proliferation defects of primordial germ cells (PGCs) and ultimately impaired fertility. We further demonstrated that MCM8 interacted with two known helicases DDX5 and DHX9, and loss of MCM8 led to R-loop accumulation by reducing the retention of these helicases at R-loops, thus inducing genome instability. Cells expressing premature ovarian insufficiency-causative mutants of MCM8 with decreased interaction with DDX5 displayed increased R-loop levels. These results show MCM8 interacts with R-loop-resolving factors to prevent R-loop-induced DNA damage, which may contribute to the maintenance of genome integrity of PGCs and reproductive reserve establishment. Our findings thus reveal an essential role for MCM8 in PGC development and improve our understanding of reproductive aging caused by genome instability in mitotic germ cells.

Citing Articles

A novel homozygous frameshift mutation in MCM8 causes primary gonadal dysgenesis in both genders.

Dong J, Zou Z, Wang W, Chen L, Ma R, Ge X J Assist Reprod Genet. 2025; .

PMID: 40064807 DOI: 10.1007/s10815-025-03443-3.

References

Alasiri S, Basit S, Wood-Trageser M, Yatsenko S, Jeffries E, Surti U . Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest. 2014; 125(1):258-62. PMC: 4382257. DOI: 10.1172/JCI78473. View

Bakkenist C, Kastan M . DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003; 421(6922):499-506. DOI: 10.1038/nature01368. View

Blackford A, Jackson S . ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Mol Cell. 2017; 66(6):801-817. DOI: 10.1016/j.molcel.2017.05.015. View

Blanton H, Radford S, McMahan S, Kearney H, Ibrahim J, Sekelsky J . REC, Drosophila MCM8, drives formation of meiotic crossovers. PLoS Genet. 2005; 1(3):e40. PMC: 1231718. DOI: 10.1371/journal.pgen.0010040. View

Bouali N, Francou B, Bouligand J, Imanci D, Dimassi S, Tosca L . New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family. Fertil Steril. 2017; 108(4):694-702. DOI: 10.1016/j.fertnstert.2017.07.015. View

Chakraborty P, Grosse F . Human DHX9 helicase preferentially unwinds RNA-containing displacement loops (R-loops) and G-quadruplexes. DNA Repair (Amst). 2011; 10(6):654-65. DOI: 10.1016/j.dnarep.2011.04.013. View

Chen C, Fernandez-Rhodes L, Brzyski R, Carlson C, Chen Z, Heiss G . Replication of loci influencing ages at menarche and menopause in Hispanic women: the Women's Health Initiative SHARe Study. Hum Mol Genet. 2011; 21(6):1419-32. PMC: 3284121. DOI: 10.1093/hmg/ddr570. View

Cristini A, Groh M, Kristiansen M, Gromak N . RNA/DNA Hybrid Interactome Identifies DXH9 as a Molecular Player in Transcriptional Termination and R-Loop-Associated DNA Damage. Cell Rep. 2018; 23(6):1891-1905. PMC: 5976580. DOI: 10.1016/j.celrep.2018.04.025. View

Cristini A, Ricci G, Britton S, Salimbeni S, Huang S, Marinello J . Dual Processing of R-Loops and Topoisomerase I Induces Transcription-Dependent DNA Double-Strand Breaks. Cell Rep. 2019; 28(12):3167-3181.e6. PMC: 8274950. DOI: 10.1016/j.celrep.2019.08.041. View

10.

DAlessandro G, Whelan D, Howard S, Vitelli V, Renaudin X, Adamowicz M . BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment. Nat Commun. 2018; 9(1):5376. PMC: 6299093. DOI: 10.1038/s41467-018-07799-2. View

11.

Dominguez D, Tsai Y, Gomez N, Jha D, Davis I, Wang Z . A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer. Cell Res. 2016; 26(8):946-62. PMC: 4973334. DOI: 10.1038/cr.2016.84. View

12.

Gambus A, Blow J . Mcm8 and Mcm9 form a dimeric complex in Xenopus laevis egg extract that is not essential for DNA replication initiation. Cell Cycle. 2013; 12(8):1225-32. PMC: 3674087. DOI: 10.4161/cc.24310. View

13.

Garcia-Muse T, Aguilera A . R Loops: From Physiological to Pathological Roles. Cell. 2019; 179(3):604-618. DOI: 10.1016/j.cell.2019.08.055. View

14.

Gozuacik D, Chami M, Lagorce D, Faivre J, Murakami Y, Poch O . Identification and functional characterization of a new member of the human Mcm protein family: hMcm8. Nucleic Acids Res. 2003; 31(2):570-9. PMC: 140502. DOI: 10.1093/nar/gkg136. View

15.

Griffin W, McKinzey D, Klinzing K, Baratam R, Eliyapura A, Trakselis M . A multi-functional role for the MCM8/9 helicase complex in maintaining fork integrity during replication stress. Nat Commun. 2022; 13(1):5090. PMC: 9427862. DOI: 10.1038/s41467-022-32583-8. View

16.

Griffin W, Trakselis M . The MCM8/9 complex: A recent recruit to the roster of helicases involved in genome maintenance. DNA Repair (Amst). 2019; 76:1-10. PMC: 9202240. DOI: 10.1016/j.dnarep.2019.02.003. View

17.

Gros J, Kumar C, Lynch G, Yadav T, Whitehouse I, Remus D . Post-licensing Specification of Eukaryotic Replication Origins by Facilitated Mcm2-7 Sliding along DNA. Mol Cell. 2015; 60(5):797-807. PMC: 4680849. DOI: 10.1016/j.molcel.2015.10.022. View

18.

Hamperl S, Bocek M, Saldivar J, Swigut T, Cimprich K . Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage Responses. Cell. 2017; 170(4):774-786.e19. PMC: 5570545. DOI: 10.1016/j.cell.2017.07.043. View

19.

Hamperl S, Cimprich K . Conflict Resolution in the Genome: How Transcription and Replication Make It Work. Cell. 2016; 167(6):1455-1467. PMC: 5141617. DOI: 10.1016/j.cell.2016.09.053. View

20.

Hatchi E, Skourti-Stathaki K, Ventz S, Pinello L, Yen A, Kamieniarz-Gdula K . BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol Cell. 2015; 57(4):636-647. PMC: 4351672. DOI: 10.1016/j.molcel.2015.01.011. View