RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly
- PMID: 18001825
- PMCID: PMC2149842
- DOI: 10.1016/j.cell.2007.09.041
RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly
Abstract
DNA-damage signaling utilizes a multitude of posttranslational modifiers as molecular switches to regulate cell-cycle checkpoints, DNA repair, cellular senescence, and apoptosis. Here we show that RNF8, a FHA/RING domain-containing protein, plays a critical role in the early DNA-damage response. We have solved the X-ray crystal structure of the FHA domain structure at 1.35 A. We have shown that RNF8 facilitates the accumulation of checkpoint mediator proteins BRCA1 and 53BP1 to the damaged chromatin, on one hand through the phospho-dependent FHA domain-mediated binding of RNF8 to MDC1, on the other hand via its role in ubiquitylating H2AX and possibly other substrates at damage sites. Moreover, RNF8-depleted cells displayed a defective G2/M checkpoint and increased IR sensitivity. Together, our study implicates RNF8 as a novel DNA-damage-responsive protein that integrates protein phosphorylation and ubiquitylation signaling and plays a critical role in the cellular response to genotoxic stress.
Figures
Similar articles
-
Crosstalk between histone modifications during the DNA damage response.Trends Cell Biol. 2009 May;19(5):207-17. doi: 10.1016/j.tcb.2009.03.001. Epub 2009 Apr 1. Trends Cell Biol. 2009. PMID: 19342239 Review.
-
RAP80 and RNF8, key players in the recruitment of repair proteins to DNA damage sites.Cancer Lett. 2008 Nov 28;271(2):179-90. doi: 10.1016/j.canlet.2008.04.046. Epub 2008 Jun 11. Cancer Lett. 2008. PMID: 18550271 Free PMC article. Review.
-
RNF8-dependent and RNF8-independent regulation of 53BP1 in response to DNA damage.J Biol Chem. 2008 May 16;283(20):13549-55. doi: 10.1074/jbc.M710197200. Epub 2008 Mar 12. J Biol Chem. 2008. PMID: 18337245
-
Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase.Science. 2007 Dec 7;318(5856):1637-40. doi: 10.1126/science.1150034. Epub 2007 Nov 15. Science. 2007. PMID: 18006705 Free PMC article.
-
RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins.Cell. 2007 Nov 30;131(5):887-900. doi: 10.1016/j.cell.2007.09.040. Epub 2007 Nov 20. Cell. 2007. PMID: 18001824
Cited by
-
DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability.Biochem J. 2024 Apr 10;481(7):515-545. doi: 10.1042/BCJ20230284. Biochem J. 2024. PMID: 38572758 Free PMC article. Review.
-
SiRNF8 Delivered by DNA Framework Nucleic Acid Effectively Sensitizes Chemotherapy in Colon Cancer.Int J Nanomedicine. 2024 Jan 6;19:171-188. doi: 10.2147/IJN.S437859. eCollection 2024. Int J Nanomedicine. 2024. PMID: 38204601 Free PMC article.
-
BRCA Mutations and Fertility Preservation.Int J Mol Sci. 2023 Dec 22;25(1):204. doi: 10.3390/ijms25010204. Int J Mol Sci. 2023. PMID: 38203374 Free PMC article. Review.
-
De novo transcriptome assembly of mouse male germ cells reveals novel genes, stage-specific bidirectional promoter activity, and noncoding RNA expression.Genome Res. 2023 Dec 21;33(12):2060-78. doi: 10.1101/gr.278060.123. Online ahead of print. Genome Res. 2023. PMID: 38129075 Free PMC article.
-
MutSβ protects common fragile sites by facilitating homology-directed repair at DNA double-strand breaks with secondary structures.Nucleic Acids Res. 2024 Feb 9;52(3):1120-1135. doi: 10.1093/nar/gkad1112. Nucleic Acids Res. 2024. PMID: 38038265 Free PMC article.
References
-
- Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434:864–870. - PubMed
-
- Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M, Gleason M, Bronson R, Lee C, Alt FW. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell. 2003;114:359–370. - PubMed
-
- Durocher D, Taylor IADS, Haire LF, Westcott SL, Jackson SP, Smerdon SJ, Yaffe MB. The molecular basis of FHA Domain:phosphopeptide binding specificity and implications for phosphodependent signaling mechanisms. Mol Cell 2000 - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous