Histone deacetylases 1 and 2 regulate DNA replication and DNA repair: potential targets for genome stability-mechanism-based therapeutics for a subset of cancers.
Histone deacetylases 1 and 2 (HDAC1,2) belong to the class I HDAC family, which are targeted by the FDA-approved small molecule HDAC inhibitors currently used in cancer therapy. HDAC1,2 are recruited to DNA break sites during DNA repair and to chromatin around forks during DNA replication. Cancer cells use DNA repair and DNA replication as survival mechanisms and to evade chemotherapy-induced cytotoxicity. Hence, it is vital to understand how HDAC1,2 function during the genome maintenance processes (DNA replication and DNA repair) in order to gain insights into the mode-of-action of HDAC inhibitors in cancer therapeutics. The first-in-class HDAC1,2-selective inhibitors and Hdac1,2 conditional knockout systems greatly facilitated dissecting the precise mechanisms by which HDAC1,2 control genome stability in normal and cancer cells. In this perspective, I summarize the findings on the mechanistic functions of class I HDACs, specifically, HDAC1,2 in genome maintenance, unanswered questions for future investigations and views on how this knowledge could be harnessed for better-targeted cancer therapeutics for a subset of cancers.
a Department of Radiation Oncology and Department of Oncological Sciences; Huntsman Cancer Institute; University of Utah School of Medicine ; Salt Lake City , UT , USA.
Srividya
S
Bhaskara
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation; D004260:DNA Repair; D004261:DNA Replication; D019008:Drug Resistance, Neoplasm; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D042822:Genomic Instability; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
DNA repair; DNA replication; Genome stability; HDAC1,2; mechanism-based cancer therapy