ATM signaling and 53BP1

Kim

Proc. Natl. Acad. Sci. U.S.A.

et al. 2009

186

193

ASC-2, a multifunctional coactivator, forms a steady-state complex, named ASCOM (for ASC-2 COMplex), that contains the histone H3-lysine-4 (H3K4)-methyltransferase MLL3 or its paralogue MLL4. Somewhat surprisingly, given prior indications of redundancy between MLL3 and MLL4, targeted inactivation of the MLL3 H3K4-methylation activity in mice is found to result in ureter epithelial tumors. Interestingly, this phenotype is exacerbated in a p53 ؉/؊ background and the tumorigenic cells are heavily immunostained for ␥H2AX, indicating a contribution of MLL3 to the DNA damage response pathway through p53. Consistent with the in vivo observations, and the demonstration of a direct interaction between p53 and ASCOM, cell-based assays have revealed that ASCOM, through ASC-2 and MLL3/4, acts as a p53 coactivator and is required for H3K4-trimethyation and expression of endogenous p53-target genes in response to the DNA damaging agent doxorubicin. In support of redundant functions for MLL3 and MLL4 for some events, siRNA-mediated down-regulation of both MLL3 and MLL4 is required to suppress doxorubicin-inducible expression of several p53-target genes. Importantly, this study identifies a specific H3K4 methytransferase complex, ASCOM, as a physiologically relevant coactivator for p53 and implicates ASCOM in the p53 tumor suppression pathway in vivo.

Section: Targeted Inactivation Of Mll3 H3k4 Methyltransferase Activitsupporting

confidence: 87%

A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4

Kim

Proc. Natl. Acad. Sci. U.S.A.

et al. 2009

186

193

“…Finally, we examined the possibility of DNA damage in hFis1 RNAi cells. It is known that ␥-H2AX, a histone H2A variant, is phosphorylated upon DNA damage and moves to the DNA damage foci (38). Likewise, the phosphorylated ␥-H2AX foci in the nuclei of hFis1-depleted cells were significantly elevated with ϳ40% of the cells on day 4 (Fig.…”

Section: Resultsmentioning

confidence: 86%

Mitochondrial Fission and Fusion Mediators, hFis1 and OPA1, Modulate Cellular Senescence

Journal of Biological Chemistry

Jeong

Lim

et al. 2007

251

189

The number and morphology of mitochondria within a cell are precisely regulated by the mitochondrial fission and fusion machinery. The human protein, hFis1, participates in mitochondrial fission by recruiting the Drp1 into the mitochondria. Using short hairpin RNA, we reduced the expression levels of hFis1 in mammalian cells. Cells lacking hFis1 showed sustained elongation of mitochondria and underwent significant cellular morphological changes, including enlargement, flattening, and increased cellular granularity. In these cells, staining for acidic senescence-associated ␤-galactosidase activity was elevated, and the rate of cell proliferation was greatly reduced, indicating that cells lacking hFis1 undergo senescence-associated phenotypic changes. Reintroduction of the hFis1 gene into hFis1-depleted cells restored mitochondrial fragmentation and suppressed senescence-associated ␤-galactosidase activity. Moreover, depletion of both hFis1 and OPA1, a critical component of mitochondrial fusion, resulted in extensive mitochondrial fragmentation and markedly rescued cells from senescence-associated phenotypic changes. Intriguingly, sustained elongation of mitochondria was associated with decreased mitochondrial membrane potential, increased reactive oxygen species production, and DNA damage. The data indicate that sustained mitochondrial elongation induces senescence-associated phenotypic changes that can be neutralized by mitochondrial fragmentation. Thus, one of the key functions of mitochondrial fission might be prevention of the sustained extensive mitochondrial elongation that triggers cellular senescence.Mitochondria are dynamic organelles that can change in number and morphology within a cell during development, the cell cycle, or when challenged with various cytotoxic conditions. Size, shape, and interconnectivity of mitochondria are determined by fusion and fission. In mammals, the key molecules for mitochondrial fission are hFis1 and Drp1. The hFis1 protein is anchored to the outer mitochondrial membrane via a C-terminal transmembrane domain, and overexpression of hFis1 was found to induce mitochondrial fragmentation (1, 2). The Drp1 is predominantly distributed in the cytoplasm and partially associates with the mitochondrial outer membrane (3). A portion of cytosolic Drp1 can be recruited to mitochondria through an interaction with hFis1 (4 -6). The opposing process, mitochondrial fusion, is controlled in mammalian cells by Mitofusins (Mfn) 3 and OPA1. Mitofusin1 and -2 (Mfn1 and Mfn2) localize on the outer membrane of mitochondria and may directly mediate mitochondrial fusion (7-9). OPA1 (optic atrophy 1) is a dynamin family GTPase that resides in the intermembrane space of mitochondria and is essential for mitochondrial fusion (10, 11). However, the functional mechanism by which these proteins cooperate to induce mitochondrial fission and fusion remains unidentified.Despite relatively intensive studies on the components of the mitochondrial fission and fusion machineries, a link between mitochondrial...

“…The DNA damage sensor protein 53BP1 has been shown to colocalize with HDAC4 in DNA damage-induced nuclear foci and cells with silenced HDAC4 exhibit marked radiosensitivity (Kao et al, 2003;Zgheib et al, 2005). This implies a role for HDAC4 in DNA repair pathways and provides evidence for another mechanism by which HDAC inhibitors could modulate cellular responses to radiation.…”

Section: Mechanisms Of Hdac Inhibitor-mediated Enhanced Radiation Senmentioning

confidence: 97%

“…It is a member of the phosphatidylinositol 3-kinase-like kinase (PIKK) family, which phosphorylate target proteins on serine or threonine followed by glutamine residues (Kim ST et al, 1999;Durocher and Jackson, 2001). The current paradigm suggests that ATM is activated following DSB-induced changes in chromatin structure which are recognized by sensor proteins including 53BP1, a DNA damage checkpoint protein conserved in all eukaryotes (Zgheib et al, 2005). Following activation ATM rapidly phosphorylates downstream substrates that are important in DSB response pathways including p53, which has key roles in cell-cycle control and apoptosis (Figure 1), MDM2, CHK1 and CHK2 which are involved in cell-cycle regulation, and BRCA1 and NBS1 which are important in DSB repair (Rotman and Shiloh, 1999;Khanna, 2000;Jackson, 2002).…”

Section: Mechanisms Of Hdac Inhibitor-mediated Enhanced Radiation Senmentioning

confidence: 99%

Modulation of cellular radiation responses by histone deacetylase inhibitors

Karagiannis

El‐Osta

2006

Oncogene

Histone deacetylase (HDAC) inhibitors are emerging as a new class of targeted cancer chemotherapeutics. Several HDAC inhibitors are currently in clinical trials and promising anticancer effects at well-tolerated doses have been observed for both hematologic and solid cancers. HDAC inhibitors have been shown to induce cell-cycle and growth arrest, differentiation and in certain cases apoptosis in cell cultures and in vivo. However, it is known that these compounds induce varying responses in different cells and biological settings, and identifying their precise mechanisms of action is an area of great interest. Important findings are continually expanding our understanding of the cellular effects of HDAC inhibitors and recent studies will be briefly outlined in this review. In addition to their intrinsic anticancer properties, numerous studies have demonstrated that HDAC inhibitors can modulate cellular responses to other cytotoxic modalities including ionizing radiation, ultraviolet radiation and chemotherapeutic drugs. Hence, there is a growing interest in potential clinical use of HDAC inhibitors in combination with conventional cancer therapies. In this review, the interaction of HDAC inhibitors with other anticancer agents is discussed. The focus of the article is on the different mechanisms by which HDAC inhibitors enhance the sensitivity of cells to the effects of ionizing radiation.