WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity

Abstract

SummaryDNA double-stranded breaks present a serious challenge for eukaryotic cells. Inability to repair breaks leads to genomic instability, carcinogenesis, and cell death. During the DSB response, mammalian chromatin undergoes reorganization demarcated by H2A.X Ser139 phosphorylation (γ-H2A.X). However, the regulation of γ-H2A.X phosphorylation and its precise role in chromatin remodeling during the repair process remain unclear. Here, we report a novel regulatory mechanism mediated by WSTF, a component of the WICH ATP-dependent chromatin remodeling complex. We show that WSTF has intrinsic tyrosine kinase activity via a domain that shares no sequence homology to any known kinase fold. We show that WSTF phosphorylates Tyr142 of H2A.X and that WSTF activity plays an important role in regulating a number of events that are critical for the DNA damage response. Our work reveals a novel mechanism that regulates the DNA damage response and expands our knowledge of domains that contain intrinsic tyrosine kinase activity.

Overexpression of a Chromatin Remodeling Factor, RSF-1/HBXAP, Correlates with Aggressive Oral Squamous Cell Carcinoma

“…At the molecular level, it has been demonstrated that regulation of nucleosome deposition is essential for transcriptional activation or repression, 28 -30 DNA replication, 31,32 DNA damage repair, 4,33,34 and cell cycle progression. [35][36][37] Chromatin remodeling factors that control DNA winding/unwinding cycles are therefore believed to be involved in these processes.…”

The role of nuclear organization in cancer

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Phosphorylation of Histone H2A at Serine 95: A Plant-Specific Mark Involved in Flowering Time Regulation and H2A.Z Deposition

“…Phosphorylation of histone H2A at serine 129 enhances the recruitment of the INO80 complex to facilitate the repair of doublestrand DNA breaks (van Attikum et al, 2004). In mammalian cells, the Williams Syndrome Transcription Factor-SNF2H (Sucrose NonFermentable 2H) chromatin remodeling complex plays a vital role in the DNA damage response and phosphorylates tyrosine 142 of H2A.X (Xiao et al, 2009). In addition to DNA damage, phosphorylation of H2A at serine 121 by Bub1 (Budding Uninhibited By Benzimidazoles 1) regulates the localization of shugoshin to prevent chromosomal instability (Kawashima et al, 2010), and phosphorylation of histone H2A at tyrosine 56 by Casein Kinase II (CK2) regulates transcriptional elongation (Basnet et al, 2014).…”