Human SHPRH is a ubiquitin ligase for Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen

I. Unk, Ildikó Hajdú, K. Fátyol, Barnabás Szakál, András Blastyák, Vladimir Bermudez, Jerard Hurwitz, Louise Prakash, Satya Prakash, L. Haracska

Research output: Contribution to journalArticle

142 Citations (Scopus)

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 3HC4 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 post-replicational 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.

Original languageEnglish
Pages (from-to)18107-18112
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number48
DOIs
Publication statusPublished - Nov 28 2006

Fingerprint

Proliferating Cell Nuclear Antigen
Ligases
Ubiquitin
DNA Replication
Ubiquitin-Protein Ligases
Fungal Proteins
Loss of Heterozygosity
Mutagenesis
Ovarian Neoplasms
Genes
Adenosine Triphosphatases
Melanoma
Neoplasms
Carcinogenesis
Yeasts
Cell Line
Proteins

Keywords

  • Postreplication repair
  • Translesion synthesis
  • Tumor suppressor

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Human SHPRH is a ubiquitin ligase for Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen. / Unk, I.; Hajdú, Ildikó; Fátyol, K.; Szakál, Barnabás; Blastyák, András; Bermudez, Vladimir; Hurwitz, Jerard; Prakash, Louise; Prakash, Satya; Haracska, L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 48, 28.11.2006, p. 18107-18112.

Research output: Contribution to journalArticle

Unk, I. ; Hajdú, Ildikó ; Fátyol, K. ; Szakál, Barnabás ; Blastyák, András ; Bermudez, Vladimir ; Hurwitz, Jerard ; Prakash, Louise ; Prakash, Satya ; Haracska, L. / Human SHPRH is a ubiquitin ligase for Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 48. pp. 18107-18112.
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AU - Unk, I.

AU - Hajdú, Ildikó

AU - Fátyol, K.

AU - Szakál, Barnabás

AU - Blastyák, András

AU - Bermudez, Vladimir

AU - Hurwitz, Jerard

AU - Prakash, Louise

AU - Prakash, Satya

AU - Haracska, L.

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AB - 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 3HC4 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 post-replicational 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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