The histone demethylase LSD1/KDM1A promotes the DNA damage response

Nima Mosammaparast, Haeyoung Kim, Benoit Laurent, Yu Zhao, Hui Jun Lim, Mona C. Majid, Sebastian Dango, Yuying Luo, Kristina Hempel, Mathew E. Sowa, Steven P. Gygi, Hanno Steen, J. Wade Harper, Bruce Yankner, Yang Shi

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

Histone demethylation is known to regulate transcription, but its role in other processes is largely unknown. We report a role for the histone demethylase LSD1/KDM1A in the DNA damage response (DDR). We show that LSD1 is recruited directly to sites of DNA damage. H3K4 dimethylation, a major substrate for LSD1, is reduced at sites of DNA damage in an LSD1-dependent manner. The E3 ubiquitin ligase RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. Although loss of LSD1 did not affect the initial formation of pH2A.X foci, 53BP1 and BRCA1 complex recruitment were reduced upon LSD1 knockdown. Mechanistically, this was likely a result of compromised histone ubiquitylation preferentially in late S/G2. Consistent with a role in the DDR, knockdown of LSD1 resulted in moderate hypersensitivity to γ-irradiation and increased homologous recombination. Our findings uncover a direct role for LSD1 in the DDR and place LSD1 downstream of RNF168 in the DDR pathway.

Original languageEnglish
Pages (from-to)457-470
Number of pages14
JournalJournal of Cell Biology
Volume203
Issue number3
DOIs
StatePublished - Nov 11 2013

Fingerprint

Dive into the research topics of 'The histone demethylase LSD1/KDM1A promotes the DNA damage response'. Together they form a unique fingerprint.

Cite this