Human SHPRH is a Ubiquitin Ligase for Mms2-Ubc13-dependent Polyubiquitylation of Proliferating Cell Nuclear Antigen

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Nov 17

PMID 17108083

Citations 132

Authors

Ildiko Unk

Ildiko Hajdu

Karoly Fatyol

Barnabas Szakal

Andras Blastyak

Vladimir Bermudez

Jerard Hurwitz

Louise Prakash

Satya Prakash

Lajos Haracska

Affiliations

Soon will be listed here.

Abstract

Human SHPRH gene is located at the 6q24 chromosomal region, and loss of heterozygosity in this region is seen in a wide variety of cancers. SHPRH is a member of the SWI/SNF family of ATPases/helicases, and it possesses a C(3)HC(4) RING motif characteristic of ubiquitin ligase proteins. In both of these features, SHPRH resembles the yeast Rad5 protein, which, together with Mms2-Ubc13, promotes replication through DNA lesions via an error-free postreplicational repair pathway. Genetic evidence in yeast has indicated a role for Rad5 as a ubiquitin ligase in mediating the Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen. Here we show that SHPRH is a functional homolog of Rad5. Similar to Rad5, SHPRH physically interacts with the Rad6-Rad18 and Mms2-Ubc13 complexes, and we show that SHPRH protein is a ubiquitin ligase indispensable for Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen. Based on these observations, we predict a role for SHPRH in promoting error-free replication through DNA lesions. Such a role for SHPRH is consistent with the observation that this gene is mutated in a number of cancer cell lines, including those from melanomas and ovarian cancers, which raises the strong possibility that SHPRH function is an important deterrent to mutagenesis and carcinogenesis in humans.

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References

Haracska L, Unk I, Johnson R, Phillips B, Hurwitz J, Prakash L . Stimulation of DNA synthesis activity of human DNA polymerase kappa by PCNA. Mol Cell Biol. 2002; 22(3):784-91. PMC: 133560. DOI: 10.1128/MCB.22.3.784-791.2002. View

Moraes T, Edwards R, McKenna S, Pastushok L, Xiao W, Glover J . Crystal structure of the human ubiquitin conjugating enzyme complex, hMms2-hUbc13. Nat Struct Biol. 2001; 8(8):669-73. DOI: 10.1038/90373. View

Sood R, Makalowska I, Galdzicki M, Hu P, Eddings E, Robbins C . Cloning and characterization of a novel gene, SHPRH, encoding a conserved putative protein with SNF2/helicase and PHD-finger domains from the 6q24 region. Genomics. 2003; 82(2):153-61. DOI: 10.1016/s0888-7543(03)00121-6. View

Stelter P, Ulrich H . Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature. 2003; 425(6954):188-91. DOI: 10.1038/nature01965. View

Haracska L, A Torres-Ramos C, Johnson R, Prakash S, Prakash L . Opposing effects of ubiquitin conjugation and SUMO modification of PCNA on replicational bypass of DNA lesions in Saccharomyces cerevisiae. Mol Cell Biol. 2004; 24(10):4267-74. PMC: 400445. DOI: 10.1128/MCB.24.10.4267-4274.2004. View

Watanabe K, Tateishi S, Kawasuji M, Tsurimoto T, Inoue H, Yamaizumi M . Rad18 guides poleta to replication stalling sites through physical interaction and PCNA monoubiquitination. EMBO J. 2004; 23(19):3886-96. PMC: 522788. DOI: 10.1038/sj.emboj.7600383. View

Johnson R, Henderson S, Petes T, Prakash S, Bankmann M, Prakash L . Saccharomyces cerevisiae RAD5-encoded DNA repair protein contains DNA helicase and zinc-binding sequence motifs and affects the stability of simple repetitive sequences in the genome. Mol Cell Biol. 1992; 12(9):3807-18. PMC: 360249. DOI: 10.1128/mcb.12.9.3807-3818.1992. View

Bailly V, Lamb J, Sung P, Prakash S, Prakash L . Specific complex formation between yeast RAD6 and RAD18 proteins: a potential mechanism for targeting RAD6 ubiquitin-conjugating activity to DNA damage sites. Genes Dev. 1994; 8(7):811-20. DOI: 10.1101/gad.8.7.811. View

Gibbs E, Kelman Z, Gulbis J, ODonnell M, Kuriyan J, Burgers P . The influence of the proliferating cell nuclear antigen-interacting domain of p21(CIP1) on DNA synthesis catalyzed by the human and Saccharomyces cerevisiae polymerase delta holoenzymes. J Biol Chem. 1997; 272(4):2373-81. DOI: 10.1074/jbc.272.4.2373. View

10.

Bailly V, Lauder S, Prakash S, Prakash L . Yeast DNA repair proteins Rad6 and Rad18 form a heterodimer that has ubiquitin conjugating, DNA binding, and ATP hydrolytic activities. J Biol Chem. 1997; 272(37):23360-5. DOI: 10.1074/jbc.272.37.23360. View

11.

Mcdonald J, Levine A, Woodgate R . The Saccharomyces cerevisiae RAD30 gene, a homologue of Escherichia coli dinB and umuC, is DNA damage inducible and functions in a novel error-free postreplication repair mechanism. Genetics. 1997; 147(4):1557-68. PMC: 1208331. DOI: 10.1093/genetics/147.4.1557. View

12.

Johnson R, Prakash S, Prakash L . Efficient bypass of a thymine-thymine dimer by yeast DNA polymerase, Poleta. Science. 1999; 283(5404):1001-4. DOI: 10.1126/science.283.5404.1001. View

13.

Johnson R, Prakash S, Prakash L . Requirement of DNA polymerase activity of yeast Rad30 protein for its biological function. J Biol Chem. 1999; 274(23):15975-7. DOI: 10.1074/jbc.274.23.15975. View

14.

Masutani C, KUSUMOTO R, Yamada A, Dohmae N, Yokoi M, Yuasa M . The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature. 1999; 399(6737):700-4. DOI: 10.1038/21447. View

15.

Johnson R, Kondratick C, Prakash S, Prakash L . hRAD30 mutations in the variant form of xeroderma pigmentosum. Science. 1999; 285(5425):263-5. DOI: 10.1126/science.285.5425.263. View

16.

Lorick K, Jensen J, Fang S, Ong A, Hatakeyama S, Weissman A . RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A. 1999; 96(20):11364-9. PMC: 18039. DOI: 10.1073/pnas.96.20.11364. View

17.

Joazeiro C, Wing S, Huang H, Leverson J, Hunter T, Liu Y . The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science. 1999; 286(5438):309-12. DOI: 10.1126/science.286.5438.309. View

18.

Prakash S, Johnson R, Prakash L . Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function. Annu Rev Biochem. 2005; 74:317-53. DOI: 10.1146/annurev.biochem.74.082803.133250. View

19.

Zhang H, Lawrence C . The error-free component of the RAD6/RAD18 DNA damage tolerance pathway of budding yeast employs sister-strand recombination. Proc Natl Acad Sci U S A. 2005; 102(44):15954-9. PMC: 1276054. DOI: 10.1073/pnas.0504586102. View

20.

Garg P, Burgers P . Ubiquitinated proliferating cell nuclear antigen activates translesion DNA polymerases eta and REV1. Proc Natl Acad Sci U S A. 2005; 102(51):18361-6. PMC: 1317920. DOI: 10.1073/pnas.0505949102. View