Microcephalin 1/BRIT1-TRF2 Interaction Promotes Telomere Replication and Repair, Linking Telomere Dysfunction to Primary Microcephaly

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Nov 18

PMID 33203878

Citations 14

Authors

Alessandro Cicconi

Rekha Rai

Xuexue Xiong

Cayla Broton

Amer Al-Hiyasat

Chunyi Hu

Siying Dong

Wenqi Sun

Jennifer Garbarino

Ranjit S Bindra

Carl Schildkraut

Yong Chen

Sandy Chang

Affiliations

Soon will be listed here.

Abstract

Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1-TRF2 complex reveals that this interaction is mediated by the MCPH1 YRLSP motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.

Citing Articles

Ustilago maydis Trf2 ensures genome stability by antagonizing Blm-mediated telomere recombination: Fine-tuning DNA repair factor activity at telomeres through opposing regulations.

Syed S, Aloe S, Sutherland J, Holloman W, Lue N PLoS Genet. 2024; 20(12):e1011515.

PMID: 39652599 PMC: 11670948. DOI: 10.1371/journal.pgen.1011515.

Loop Extrusion Machinery Impairments in Models and Disease.

Ryzhkova A, Maltseva E, Battulin N, Kabirova E Cells. 2024; 13(22).

PMID: 39594644 PMC: 11592926. DOI: 10.3390/cells13221896.

Replication stress as a driver of cellular senescence and aging.

Herr L, Schaffer E, Fuchs K, Datta A, Brosh Jr R Commun Biol. 2024; 7(1):616.

PMID: 38777831 PMC: 11111458. DOI: 10.1038/s42003-024-06263-w.

The emerging role of MCPH1/BRIT1 in carcinogenesis.

Alsolami M, Aboalola D, Malibari D, Alghamdi T, Alshekhi W, Jad H Front Oncol. 2023; 13:1047588.

PMID: 36845691 PMC: 9951231. DOI: 10.3389/fonc.2023.1047588.

Congenital Microcephaly: A Debate on Diagnostic Challenges and Etiological Paradigm of the Shift from Isolated/Non-Syndromic to Syndromic Microcephaly.

Asif M, Abdullah U, Nurnberg P, Tinschert S, Hussain M Cells. 2023; 12(4).

PMID: 36831309 PMC: 9954724. DOI: 10.3390/cells12040642.

References

Takai H, Smogorzewska A, de Lange T . DNA damage foci at dysfunctional telomeres. Curr Biol. 2003; 13(17):1549-56. DOI: 10.1016/s0960-9822(03)00542-6. View

Evrony G, Cordero D, Shen J, Partlow J, Yu T, Rodin R . Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor as the cause of microcephaly-micromelia syndrome. Genome Res. 2017; 27(8):1323-1335. PMC: 5538549. DOI: 10.1101/gr.219899.116. View

Bryant H, Schultz N, Thomas H, Parker K, Flower D, Lopez E . Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005; 434(7035):913-7. DOI: 10.1038/nature03443. View

Liang Y, Gao H, Lin S, Goss J, Du C, Li K . Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model. Oncogene. 2014; 34(33):4368-78. PMC: 4417661. DOI: 10.1038/onc.2014.367. View

de Vries B, Winter R, Schinzel A, van Ravenswaaij-Arts C . Telomeres: a diagnosis at the end of the chromosomes. J Med Genet. 2003; 40(6):385-98. PMC: 1735506. DOI: 10.1136/jmg.40.6.385. View

Artandi S, DePinho R . Telomeres and telomerase in cancer. Carcinogenesis. 2009; 31(1):9-18. PMC: 3003493. DOI: 10.1093/carcin/bgp268. View

Huertas P . DNA resection in eukaryotes: deciding how to fix the break. Nat Struct Mol Biol. 2010; 17(1):11-6. PMC: 2850169. DOI: 10.1038/nsmb.1710. View

Poole L, Zhao R, Glick G, Lovejoy C, Eischen C, Cortez D . SMARCAL1 maintains telomere integrity during DNA replication. Proc Natl Acad Sci U S A. 2015; 112(48):14864-9. PMC: 4672769. DOI: 10.1073/pnas.1510750112. View

Ye J, Lenain C, Bauwens S, Rizzo A, Saint-Leger A, Poulet A . TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage. Cell. 2010; 142(2):230-42. DOI: 10.1016/j.cell.2010.05.032. View

10.

Rai R, Gu P, Broton C, Kumar-Sinha C, Chen Y, Chang S . The Replisome Mediates A-NHEJ Repair of Telomeres Lacking POT1-TPP1 Independently of MRN Function. Cell Rep. 2019; 29(11):3708-3725.e5. PMC: 7001145. DOI: 10.1016/j.celrep.2019.11.012. View

11.

Greider C . Telomere length regulation. Annu Rev Biochem. 1996; 65:337-65. DOI: 10.1146/annurev.bi.65.070196.002005. View

12.

Chen J, Ingham N, Clare S, Raisen C, Vancollie V, Ismail O . Mcph1-deficient mice reveal a role for MCPH1 in otitis media. PLoS One. 2013; 8(3):e58156. PMC: 3596415. DOI: 10.1371/journal.pone.0058156. View

13.

Wan B, Yin J, Horvath K, Sarkar J, Chen Y, Wu J . SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. Cell Rep. 2013; 4(5):861-9. PMC: 4334113. DOI: 10.1016/j.celrep.2013.08.017. View

14.

Rickman K, Smogorzewska A . Advances in understanding DNA processing and protection at stalled replication forks. J Cell Biol. 2019; 218(4):1096-1107. PMC: 6446843. DOI: 10.1083/jcb.201809012. View

15.

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

16.

Rai R, Zheng H, He H, Luo Y, Multani A, Carpenter P . The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres. EMBO J. 2010; 29(15):2598-610. PMC: 2928694. DOI: 10.1038/emboj.2010.142. View

17.

Rai R, Hu C, Broton C, Chen Y, Lei M, Chang S . NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres. Mol Cell. 2017; 65(5):801-817.e4. PMC: 5639704. DOI: 10.1016/j.molcel.2017.01.016. View

18.

Wu P, van Overbeek M, Rooney S, de Lange T . Apollo contributes to G overhang maintenance and protects leading-end telomeres. Mol Cell. 2010; 39(4):606-17. PMC: 2929323. DOI: 10.1016/j.molcel.2010.06.031. View

19.

Przetocka S, Porro A, Bolck H, Walker C, Lezaja A, Trenner A . CtIP-Mediated Fork Protection Synergizes with BRCA1 to Suppress Genomic Instability upon DNA Replication Stress. Mol Cell. 2018; 72(3):568-582.e6. DOI: 10.1016/j.molcel.2018.09.014. View

20.

Rai R, Chen Y, Lei M, Chang S . TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nat Commun. 2016; 7:10881. PMC: 4785230. DOI: 10.1038/ncomms10881. View