HDACs and DNA Damage Repair Genome Integrity

Proper DNA repair is important for the elimination of gene mutation and maintenance of genome integrity during cell growth. Failure or abnormity of DNA repair may result in genome instability, such as deletion of tumor suppresser genes or amplification of oncogenes, and thus lead to tumorigenesis (Khanna and Jackson 2001; Risinger and Groden 2004). One of the most important functions of HDACs, besides the role of transcriptional repression, is their regulation of DNA damage responses (DDR). HDAC(s) could directly deacetylate some DNA repair proteins and alter their functions.

SIRT1 is the leading HDAC involved in the regulation of DNA repair proteins through deacetylation, suggesting that it plays significant roles in DNA repair and genome integrity. As mentioned before, Ku70 and p53, the two important effectors downstream of the repair signal cascades initiated by double strand break (DSB) damage, are directly deacetylated and inhibited by SIRT1. SIRT1 also deacetylates many other DDR proteins. NBS1 is the regulatory subunit of MRE11-RAD50-NBS1 (MRN), a conserved nuclease complex that exhibits properties of a DNA damage sensor and is critical for the cellular response to DNA DSBs. Phosphorylation of NBS1 by the ATM kinase is essential for its activation in response to DNA damage (Buscemi et al. 2001). Our previous work demonstrated that NBS1 is an acetylated protein and that its acetylation level is tightly regulated by SIRT1. SIRT1 associates with the MRN complex and keeps NBS1 in a hypoacetylated state, which is required for the ionizing radiation-induced phosphorylation of NBS1 at Ser343 and, in turn, activation. This work indicated the presence of crosstalk between two different PTMs in NBS1 and strongly suggested the key role of deacetylation of NBS1 by SIRT1 in the dynamic regulation of the DDR and maintenance of genomic stability (Yuan et al. 2007).

SIRT1 also regulates WRN (Werner syndrome protein)-mediated cellular responses to DNA damage. WRN is a member of the RecQ DNA helicase family and involved in premature aging and cancer (Opresko et al. 2007). WRN could be acetylated by acetyltransferase CBP/p300 and deacetylated by SIRT1 in vitro and in vivo. SIRT1-mediated deacetylation regulates the cellular localization of WRN, and also its helicase and exonuclease activities (Li et al. 2008). Furthermore, SIRT1 deacetylation was required for SIRT1-mediated homologous recombination (HR) in DSB repair (Uhl et al. 2010). In addition, SIRT1 is capable of deacetylating and interplaying with poly (ADP-ribose) polymerase 1 (PARP-1) in maintaining genome integrity (El Ramy et al. 2009). These results provide sound evidence of a link between SIRT1 and HR with possible implications for genomic stability during aging and tumorigenesis.

Some other DNA repair proteins (e.g., DNA glycosylases, Flap endonuclease 1 [FEN1], and Dna2 endonuclease/helicase [Dna2]) are also acetylated, and acetyla-tion changes their biological activities (Balakrishnan et al. 2010; Bhakat et al. 2004, 2006; Friedrich-Heineken et al. 2003; Hasan et al. 2001). However, the HDAC responsible for the deacetylation of these proteins is unknown.

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