DNA Replication Initiation Factor RECQ4 Possesses a Role in Antagonizing DNA Replication Initiation

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Mar 4

PMID 36871012

Authors

Xiaohua Xu

Chou-Wei Chang

Min Li

Kenneth Omabe

Nhung Le

Yi-Hsuan Chen

Feng Liang

Yilun Liu

Affiliations

Soon will be listed here.

Abstract

Deletion of the conserved C-terminus of the Rothmund-Thomson syndrome helicase RECQ4 is highly tumorigenic. However, while the RECQ4 N-terminus is known to facilitate DNA replication initiation, the function of its C-terminus remains unclear. Using an unbiased proteomic approach, we identify an interaction between the RECQ4 N-terminus and the anaphase-promoting complex/cyclosome (APC/C) on human chromatin. We further show that this interaction stabilizes APC/C co-activator CDH1 and enhances APC/C-dependent degradation of the replication inhibitor Geminin, allowing replication factors to accumulate on chromatin. In contrast, the function is blocked by the RECQ4 C-terminus, which binds to protein inhibitors of APC/C. A cancer-prone, C-terminal-deleted RECQ4 mutation increases origin firing frequency, accelerates G/S transition, and supports abnormally high DNA content. Our study reveals a role of the human RECQ4 C-terminus in antagonizing its N-terminus, thereby suppressing replication initiation, and this suppression is impaired by oncogenic mutations.

Citing Articles

RECQ4-MUS81 interaction contributes to telomere maintenance with implications to Rothmund-Thomson syndrome.

Ashraf R, Polasek-Sedlackova H, Marini V, Prochazkova J, Hasanova Z, Zacpalova M Nat Commun. 2025; 16(1):1302.

PMID: 39900600 PMC: 11791078. DOI: 10.1038/s41467-025-56518-1.

Rothmund-Thomson syndrome, a disorder far from solved.

Martins D, di Lazzaro Filho R, Bertola D, Hoch N Front Aging. 2023; 4:1296409.

PMID: 38021400 PMC: 10676203. DOI: 10.3389/fragi.2023.1296409.

References

Sivaprasad U, Machida Y, Dutta A . APC/C--the master controller of origin licensing?. Cell Div. 2007; 2:8. PMC: 1810247. DOI: 10.1186/1747-1028-2-8. View

Chang C, Xu X, Li M, Xin D, Ding L, Wang Y . Pathogenic mutations reveal a role of RECQ4 in mitochondrial RNA:DNA hybrid formation and resolution. Sci Rep. 2020; 10(1):17033. PMC: 7552406. DOI: 10.1038/s41598-020-74095-9. View

Lee H, Davidson J, Duronio R . Endoreplication: polyploidy with purpose. Genes Dev. 2009; 23(21):2461-77. PMC: 2779750. DOI: 10.1101/gad.1829209. View

McGarry T, Kirschner M . Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell. 1998; 93(6):1043-53. DOI: 10.1016/s0092-8674(00)81209-x. View

Smits A, Ziebell F, Joberty G, Zinn N, Mueller W, Clauder-Munster S . Biological plasticity rescues target activity in CRISPR knock outs. Nat Methods. 2019; 16(11):1087-1093. DOI: 10.1038/s41592-019-0614-5. View

Gonzalez M, Tachibana K, Adams D, van der Weyden L, Hemberger M, Coleman N . Geminin is essential to prevent endoreduplication and to form pluripotent cells during mammalian development. Genes Dev. 2006; 20(14):1880-4. PMC: 1522086. DOI: 10.1101/gad.379706. View

Kellermayer R . The versatile RECQL4. Genet Med. 2006; 8(4):213-6. DOI: 10.1097/01.gim.0000214457.58378.1a. View

Ichikawa K, Noda T, Furuichi Y . [Preparation of the gene targeted knockout mice for human premature aging diseases, Werner syndrome, and Rothmund-Thomson syndrome caused by the mutation of DNA helicases]. Nihon Yakurigaku Zasshi. 2002; 119(4):219-26. DOI: 10.1254/fpj.119.219. View

Icard P, Wu Z, Fournel L, Coquerel A, Lincet H, Alifano M . ATP citrate lyase: A central metabolic enzyme in cancer. Cancer Lett. 2019; 471:125-134. DOI: 10.1016/j.canlet.2019.12.010. View

10.

Gandarillas A, Molinuevo R, Sanz-Gomez N . Mammalian endoreplication emerges to reveal a potential developmental timer. Cell Death Differ. 2018; 25(3):471-476. PMC: 5864232. DOI: 10.1038/s41418-017-0040-0. View

11.

Woodward A, Gohler T, Luciani M, Oehlmann M, Ge X, Gartner A . Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress. J Cell Biol. 2006; 173(5):673-83. PMC: 2063885. DOI: 10.1083/jcb.200602108. View

12.

Kitao S, Ohsugi I, Ichikawa K, Goto M, Furuichi Y, Shimamoto A . Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes. Genomics. 1999; 54(3):443-52. DOI: 10.1006/geno.1998.5595. View

13.

Schrock M, Stromberg B, Scarberry L, Summers M . APC/C ubiquitin ligase: Functions and mechanisms in tumorigenesis. Semin Cancer Biol. 2020; 67(Pt 2):80-91. PMC: 7483777. DOI: 10.1016/j.semcancer.2020.03.001. View

14.

Sanders E, Nguyen P, Rogers C, Bochman M . Comprehensive Synthetic Genetic Array Analysis of Alleles That Interact with Mutation of the RecQ Helicases Hrq1 and Sgs1. G3 (Bethesda). 2020; 10(12):4359-4368. PMC: 7718751. DOI: 10.1534/g3.120.401709. View

15.

Tada S . Cdt1 and geminin: role during cell cycle progression and DNA damage in higher eukaryotes. Front Biosci. 2006; 12:1629-41. DOI: 10.2741/2175. View

16.

Larizza L, Roversi G, Volpi L . Rothmund-Thomson syndrome. Orphanet J Rare Dis. 2010; 5:2. PMC: 2826297. DOI: 10.1186/1750-1172-5-2. View

17.

Bashir T, Dorrello N, Amador V, Guardavaccaro D, Pagano M . Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature. 2004; 428(6979):190-3. DOI: 10.1038/nature02330. View

18.

Yang Y, Lacefield S . Bub3 activation and inhibition of the APC/C. Cell Cycle. 2016; 15(1):1-2. PMC: 4825784. DOI: 10.1080/15384101.2015.1106746. View

19.

Zhang S, Tischer T, Barford D . Cyclin A2 degradation during the spindle assembly checkpoint requires multiple binding modes to the APC/C. Nat Commun. 2019; 10(1):3863. PMC: 6712056. DOI: 10.1038/s41467-019-11833-2. View

20.

Abe T, Yoshimura A, Hosono Y, Tada S, Seki M, Enomoto T . The N-terminal region of RECQL4 lacking the helicase domain is both essential and sufficient for the viability of vertebrate cells. Role of the N-terminal region of RECQL4 in cells. Biochim Biophys Acta. 2011; 1813(3):473-9. DOI: 10.1016/j.bbamcr.2011.01.001. View