The Nuclear Oncogene SET Controls DNA Repair by KAP1 and HP1 Retention to Chromatin

Abstract

Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair. SET interacts with the Kruppel-associated box (KRAB)-associated co-repressor KAP1, and its overexpression results in the sustained retention of KAP1 and Heterochromatin protein 1 (HP1) on chromatin. Our results are consistent with a model in which SET-mediated chromatin compaction triggers an inhibition of DNA end resection and HR.

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

“…In agreement with the oncogenic function of SET/TAF-Ib, its overexpression in tumor cells blocks the genotoxic stress-induced apoptosis by inhibiting p53 [125] and Ku70 [130]. Thus, SET/TAF-Ib is a key factor in chromatin remodeling and DNA repair regulation [131,132], processes that require an accurate regulation of chromatin dynamics [115]. We observed that mitochondrial Cc reaches the human cell nucleus soon after DNA breaks appear-even before activation of caspases in the cytoplasm-and binds to SET/TAF-Ib, thereby inhibiting its histone chaperone activity [119].…”

Distinct roles of the histone chaperones NAP1 and NRP and the chromatin‐remodeling factor INO80 in somatic homologous recombination in Arabidopsis thaliana

“…This is in sharp contrast to the situation in animals where loss of NAP1 impairs normal organism development (Lankenau et al, 2003;Rogner et al, 2000). Furthermore, in human cell lines, while NAP1 positively regulates HR (Machida et al, 2014), SET/TAF-I/I 2 PP2A /INHAT has recently been reported to play a repressor role in HR and the DNA damage response (Kalousi et al, 2015). Our finding of a non-essential role of AtNAP1 and NRP in plant growth and development also contrasts with the drastic and pleiotropic growth and developmental defects described for mutants of other types of histone chaperones, including CHROMATIN ASSEMBLY FACTOR-1 (CAF-1; Kaya et al, 2001), ANTI-SILENCING FUNCTION1 (ASF1; Zhu et al, 2011;Lario et al, 2013;Weng et al, 2014) and FACILITATES CHROMATIN TRANSCRIPTION (FACT; Lolas et al, 2010).…”

“…This is in sharp contrast to the situation in animals where loss of NAP1 impairs normal organism development (Lankenau et al ., ; Rogner et al ., ). Furthermore, in human cell lines, while NAP1 positively regulates HR (Machida et al ., ), SET/TAF‐I/I 2 PP2A /INHAT has recently been reported to play a repressor role in HR and the DNA damage response (Kalousi et al ., ).…”

Phospho-H1 Decorates the Inter-chromatid Axis and Is Evicted along with Shugoshin by SET during Mitosis

“…Cellular studies on SET have revealed a wide range of functions including transcriptional regulation, modulation of chromosome condensation and cohesion during meiosis, as well as in anti-apoptotic and DNA repair signaling pathways (Chambon et al, 2013; Fan et al, 2003; Kalousi et al, 2015; Matsumoto et al, 1999). Yet, the functional contribution of SET to these processes and whether/how its property as a chaperone integrates into these pathways is unclear.…”