SETD1A methyltransferase is physically and functionally linked to the DNA damage repair protein RAD18

Manal Alsulami, Nayla Munawar, Eugene DIllon, Giorgio Oliviero, Kieran Wynne, Mona Alsolami, Catherine Moss, Peadar Gaora, Fergal O'Meara, David Cotter, Gerard Cagney

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

SETD1A is a SET domain-containing methyltransferase involved in epigenetic regulation of transcription. It is the main catalytic component of a multiprotein complex that methylates lysine 4 of histone H3, a histone mark associated with gene activation. In humans, six related protein complexes with partly nonredundant cellular functions share several protein subunits but are distinguished by unique catalytic SET-domain proteins. We surveyed physical interactions of the SETD1A-complex using endogenous immunoprecipitation followed by label-free quantitative proteomics on three subunits: SETD1A, RBBP5, and ASH2L. Surprisingly, SETD1A, but not RBBP5 or ASH2L, was found to interact with the DNA damage repair protein RAD18. Reciprocal RAD18 immunoprecipitation experiments confirmed the interaction with SETD1A, whereas size exclusion and protein network analysis suggested an interaction independent of the main SETD1A complex. We found evidence of SETD1A and RAD18 influence on mutual gene expression levels. Further, knockdown of the genes individually showed a DNA damage repair phenotype, whereas simultaneous knockdown resulted in an epistatic effect. This adds to a growing body of work linking epigenetic enzymes to processes involved in genome stability.

Original languageEnglish
Pages (from-to)1428-1436
Number of pages9
JournalMolecular and Cellular Proteomics
Volume18
Issue number7
DOIs
Publication statusPublished - 2019
Externally publishedYes

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology

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