TY - JOUR
T1 - Histone acetyltransferase MOF orchestrates outcomes at the crossroad of oncogenesis, DNA damage response, proliferation, and stem cell development
AU - Singh, Mayank
AU - Bacolla, Albino
AU - Chaudhary, Shilpi
AU - Hunt, Clayton R.
AU - Pandita, Shruti
AU - Chauhan, Ravi
AU - Gupta, Ashna
AU - Tainer, John A.
AU - Pandita, Tej K.
N1 - Funding Information:
This work was supported by grants GM109768-06 and RO1 CA129537 (T.K.P.) plus CA092584 and R35 CA220430 (J.A.T.) from the National Institutes of Health. J.A.T. is also supported by Cancer Prevention Research Institute of Texas (CPRIT) grants RP180813 and RP130397 and a Robert A. Welch Chemistry Chair. The research used resources from the Texas Advanced Computing Center (TACC) supported by National Science Foundation grant ACI-1134872. We declare no competing interests.
Publisher Copyright:
© 2020 American Society for Microbiology. All Rights Reserved.
PY - 2020/8/28
Y1 - 2020/8/28
N2 - The DNA and protein complex known as chromatin is subject to posttranslational modifications (PTMs) that regulate cellular functions such that PTM dysregulation can lead to disease, including cancer. One critical PTM is acetylation/ deacetylation, which is being investigated as a means to develop targeted cancer therapies. The histone acetyltransferase (HAT) family of proteins performs histone acetylation. In humans, MOF (hMOF), a member of the MYST family of HATs, acetylates histone H4 at lysine 16 (H4K16ac). MOF-mediated acetylation plays a critical role in the DNA damage response (DDR) and embryonic stem cell development. Functionally, MOF is found in two distinct complexes: NSL (nonspecific lethal) in humans and MSL (male-specific lethal) in flies. The NSL complex is also able to acetylate additional histone H4 sites. Dysregulation of MOF activity occurs in multiple cancers, including ovarian cancer, medulloblastoma, breast cancer, colorectal cancer, and lung cancer. Bioinformatics analysis of KAT8, the gene encoding hMOF, indicated that it is highly overexpressed in kidney tumors as part of a concerted gene coexpression program that can support high levels of chromosome segregation and cell proliferation. The linkage between MOF and tumor proliferation suggests that there are additional functions of MOF that remain to be discovered.
AB - The DNA and protein complex known as chromatin is subject to posttranslational modifications (PTMs) that regulate cellular functions such that PTM dysregulation can lead to disease, including cancer. One critical PTM is acetylation/ deacetylation, which is being investigated as a means to develop targeted cancer therapies. The histone acetyltransferase (HAT) family of proteins performs histone acetylation. In humans, MOF (hMOF), a member of the MYST family of HATs, acetylates histone H4 at lysine 16 (H4K16ac). MOF-mediated acetylation plays a critical role in the DNA damage response (DDR) and embryonic stem cell development. Functionally, MOF is found in two distinct complexes: NSL (nonspecific lethal) in humans and MSL (male-specific lethal) in flies. The NSL complex is also able to acetylate additional histone H4 sites. Dysregulation of MOF activity occurs in multiple cancers, including ovarian cancer, medulloblastoma, breast cancer, colorectal cancer, and lung cancer. Bioinformatics analysis of KAT8, the gene encoding hMOF, indicated that it is highly overexpressed in kidney tumors as part of a concerted gene coexpression program that can support high levels of chromosome segregation and cell proliferation. The linkage between MOF and tumor proliferation suggests that there are additional functions of MOF that remain to be discovered.
KW - Cancer
KW - DDR
KW - Histone acetyltransferase
KW - MOF
KW - Stem cell
KW - Cell Nucleus/metabolism
KW - Chromatin/metabolism
KW - Humans
KW - Cell Proliferation/physiology
KW - Histone Acetyltransferases/metabolism
KW - Carcinogenesis/metabolism
KW - Cell Transformation, Neoplastic/metabolism
KW - Histones/metabolism
KW - Lung Neoplasms/metabolism
KW - Cell Differentiation/physiology
KW - Nuclear Proteins/metabolism
KW - Protein Processing, Post-Translational
KW - Acetylation
KW - DNA Damage
KW - Embryonic Stem Cells/cytology
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U2 - 10.1128/MCB.00232-20
DO - 10.1128/MCB.00232-20
M3 - Review article
C2 - 32661120
AN - SCOPUS:85090027615
SN - 0270-7306
VL - 40
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 18
M1 - e00232-20
ER -