Systematic Analysis of DNA Crosslink Repair Pathways During Development and Aging in Caenorhabditis Elegans

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2017 Sep 22

PMID 28934497

Citations 18

Authors

David M Wilson 3rd

Matthias Rieckher

Ashley B Williams

Bjorn Schumacher

Affiliations

Soon will be listed here.

Abstract

DNA interstrand crosslinks (ICLs) are generated by endogenous sources and chemotherapeutics, and pose a threat to genome stability and cell survival. Using Caenorhabditis elegans mutants, we identify DNA repair factors that protect against the genotoxicity of ICLs generated by trioxsalen/ultraviolet A (TMP/UVA) during development and aging. Mutations in nucleotide excision repair (NER) components (e.g. XPA-1 and XPF-1) imparted extreme sensitivity to TMP/UVA relative to wild-type animals, manifested as developmental arrest, defects in adult tissue morphology and functionality, and shortened lifespan. Compensatory roles for global-genome (XPC-1) and transcription-coupled (CSB-1) NER in ICL sensing were exposed. The analysis also revealed contributions of homologous recombination (BRC-1/BRCA1), the MUS-81, EXO-1, SLX-1 and FAN-1 nucleases, and the DOG-1 (FANCJ) helicase in ICL resolution, influenced by the replicative-status of the cell/tissue. No obvious or critical role in ICL repair was seen for non-homologous end-joining (cku-80) or base excision repair (nth-1, exo-3), the Fanconi-related proteins BRC-2 (BRCA2/FANCD1) and FCD-2 (FANCD2), the WRN-1 or HIM-6 (BLM) helicases, or the GEN-1 or MRT-1 (SNM1) nucleases. Our efforts uncover replication-dependent and -independent ICL repair networks, and establish nematodes as a model for investigating the repair and consequences of DNA crosslinks in metazoan development and in adult post-mitotic and proliferative germ cells.

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References

Klein Douwel D, Boonen R, Long D, Szypowska A, Raschle M, Walter J . XPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4. Mol Cell. 2014; 54(3):460-71. PMC: 5067070. DOI: 10.1016/j.molcel.2014.03.015. View

Niedernhofer L, Daniels J, Rouzer C, Greene R, Marnett L . Malondialdehyde, a product of lipid peroxidation, is mutagenic in human cells. J Biol Chem. 2003; 278(33):31426-33. DOI: 10.1074/jbc.M212549200. View

Meier B, Barber L, Liu Y, Shtessel L, Boulton S, Gartner A . The MRT-1 nuclease is required for DNA crosslink repair and telomerase activity in vivo in Caenorhabditis elegans. EMBO J. 2009; 28(22):3549-63. PMC: 2782091. DOI: 10.1038/emboj.2009.278. View

Alekseev S, Coin F . Orchestral maneuvers at the damaged sites in nucleotide excision repair. Cell Mol Life Sci. 2015; 72(11):2177-86. PMC: 11113351. DOI: 10.1007/s00018-015-1859-5. View

Jones M, Huang T . The Fanconi anemia pathway in replication stress and DNA crosslink repair. Cell Mol Life Sci. 2012; 69(23):3963-74. PMC: 3890373. DOI: 10.1007/s00018-012-1051-0. View

Zhao J, Jain A, Iyer R, Modrich P, Vasquez K . Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks. Nucleic Acids Res. 2009; 37(13):4420-9. PMC: 2715249. DOI: 10.1093/nar/gkp399. View

Lans H, Lindvall J, Thijssen K, Karambelas A, Cupac D, Fensgard O . DNA damage leads to progressive replicative decline but extends the life span of long-lived mutant animals. Cell Death Differ. 2013; 20(12):1709-18. PMC: 3824592. DOI: 10.1038/cdd.2013.126. View

Johnson K, Price N, Wang J, Fekry M, Dutta S, Seiner D . On the formation and properties of interstrand DNA-DNA cross-links forged by reaction of an abasic site with the opposing guanine residue of 5'-CAp sequences in duplex DNA. J Am Chem Soc. 2012; 135(3):1015-25. PMC: 4012394. DOI: 10.1021/ja308119q. View

Sarbajna S, West S . Holliday junction processing enzymes as guardians of genome stability. Trends Biochem Sci. 2014; 39(9):409-19. DOI: 10.1016/j.tibs.2014.07.003. View

10.

Kuraoka I, Kobertz W, Ariza R, Biggerstaff M, Essigmann J, Wood R . Repair of an interstrand DNA cross-link initiated by ERCC1-XPF repair/recombination nuclease. J Biol Chem. 2000; 275(34):26632-6. DOI: 10.1074/jbc.C000337200. View

11.

Niedernhofer L, Garinis G, Raams A, Lalai A, Robinson A, Appeldoorn E . A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature. 2006; 444(7122):1038-43. DOI: 10.1038/nature05456. View

12.

Huang J, Liu S, Bellani M, Thazhathveetil A, Ling C, de Winter J . The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand crosslinks. Mol Cell. 2013; 52(3):434-46. PMC: 3880019. DOI: 10.1016/j.molcel.2013.09.021. View

13.

Hinz J . Role of homologous recombination in DNA interstrand crosslink repair. Environ Mol Mutagen. 2010; 51(6):582-603. DOI: 10.1002/em.20577. View

14.

Hodskinson M, Silhan J, Crossan G, Garaycoechea J, Mukherjee S, Johnson C . Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair. Mol Cell. 2014; 54(3):472-84. PMC: 4017094. DOI: 10.1016/j.molcel.2014.03.014. View

15.

Roy U, Scharer O . Involvement of translesion synthesis DNA polymerases in DNA interstrand crosslink repair. DNA Repair (Amst). 2016; 44:33-41. PMC: 5524570. DOI: 10.1016/j.dnarep.2016.05.004. View

16.

Wu Q, Christensen L, Legerski R, Vasquez K . Mismatch repair participates in error-free processing of DNA interstrand crosslinks in human cells. EMBO Rep. 2005; 6(6):551-7. PMC: 1369090. DOI: 10.1038/sj.embor.7400418. View

17.

Youds J, Barber L, Ward J, Collis S, ONeil N, Boulton S . DOG-1 is the Caenorhabditis elegans BRIP1/FANCJ homologue and functions in interstrand cross-link repair. Mol Cell Biol. 2007; 28(5):1470-9. PMC: 2258786. DOI: 10.1128/MCB.01641-07. View

18.

Smogorzewska A, Desetty R, Saito T, Schlabach M, Lach F, Sowa M . A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol Cell. 2010; 39(1):36-47. PMC: 2919743. DOI: 10.1016/j.molcel.2010.06.023. View

19.

Michl J, Zimmer J, Tarsounas M . Interplay between Fanconi anemia and homologous recombination pathways in genome integrity. EMBO J. 2016; 35(9):909-23. PMC: 4865030. DOI: 10.15252/embj.201693860. View

20.

Crossan G, Patel K . The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA. J Pathol. 2011; 226(2):326-37. DOI: 10.1002/path.3002. View