Homeodomain Proteins Directly Regulate ATM Kinase Activity

Johnson, Tanya E.; Lee, Ji-Hoon; Myler, Logan R.; Zhou, Yi; Mosley, Trenell J.; Yang, Soo-Hyun; Uprety, Nadima; Kim, Jonghwan; Paull, Tanya T.

doi:10.1016/j.celrep.2018.06.089

Cited by 7 publications

(3 citation statements)

References 64 publications

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“…We report here that, in the absence of ZEB1, these three key chromatin-contracting elements-macroH2A.1, PRDM2, and H3K9me2/3-are all significantly increased, suggesting that one role of ZEB1 is to counteract the establishment of a BRCA1-permissive environment; the near-immediate localization of ZEB1 to a LASER lesion further supports this. Such activity is further supported by our finding that ZEB1s homeodomain is required for the pro-NHEJ/anti-HR fluorescence output of the EJ-DR pathway choice cell line ( Fig 3A), suggesting that, like many homeodomain-harboring proteins, ZEB1 may serve as a block to ATM activity in this context, favoring DNA-PK-mediated direct end-joining over DSB repair by the HR pathway (52).…”

Section: Discussionsupporting

confidence: 67%

ZEB1 is Required for NHEJ-Mediated DSB Repair in Euchromatin

Genetta

Abbas

Pandita

et al. 2020

Preprint

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Ionizing radiation-induced DSBs are repaired primarily by the Non-Homologous End Joining (NHEJ) pathway, but the details of how this is regulated in different chromatin contexts are far from understood. We have discovered a novel response to DSBs that promotes NHEJ selectively in euchromatin, based on a novel interaction between the EMT-inducing transcriptional repressor ZEB1, and the wellstudied NHEJ-promoting DNA repair factor 53BP1. Using a number of approaches, we have discovered that the ZEB1-53BP1 association is amplified following exposure of cells to IR and that they co-localize at IR-induced foci (IRIF). Depletion of ZEB1 enhances radio-sensitivity and increases IR-induced chromosomal aberrations in an ATM-independent manner. The very rapid recruitment-within 2 seconds-of ZEB1 to euchromatic DSBs is like-wise ATM-independent, but DNA-PK-dependent and is required for subsequent recruitment of 53BP1. ZEB1 promotes NHEJ and inhibits HR through its homeodomain by inducing 53BP1permissive, pro-NHEJ/anti-HR chromatin modifications. Lastly, depletion of ZEB1 increases hyper-resection at DSBs and inhibits physiological DSB repair. These results support the argument that ZEB1 plays an essential role in DSB repair in euchromatin by establishing a 53BP1-permissive/pro-NHEJ chromatin environment.

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Section: Discussionsupporting

confidence: 67%

ZEB1 is Required for NHEJ-Mediated DSB Repair in Euchromatin

Genetta

Abbas

Pandita

et al. 2020

Preprint

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“…Our present results, together with our previous work (13), indicate that this PAR-dependent recruitment mechanism can account for the accumulation of CHD4, and also probably CHD3, at the sites of damage. Future work will be necessary to establish whether this recruitment mode also holds true for other DNA-binding repair proteins or for regulatory factors modulating the activity of these repair proteins such as the recently identified regulation of the Ataxia-telangiectasia mutated (ATM) kinase by homeobox transcription factors (69). Furthermore, the recruitment via enhanced DNA binding of proteins displaying functions in transcription modulation may contribute to the early repression of transcription at the sites of DNA damage (70).…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose)-dependent chromatin unfolding facilitates the association of DNA-binding proteins with DNA at sites of damage

Smith

Lebeaupin

Juhász

et al. 2019

Nucleic Acids Research

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The addition of poly(ADP-ribose) (PAR) chains along the chromatin fiber due to PARP1 activity regulates the recruitment of multiple factors to sites of DNA damage. In this manuscript, we investigated how, besides direct binding to PAR, early chromatin unfolding events controlled by PAR signaling contribute to recruitment to DNA lesions. We observed that different DNA-binding, but not histone-binding, domains accumulate at damaged chromatin in a PAR-dependent manner, and that this recruitment correlates with their affinity for DNA. Our findings indicate that this recruitment is promoted by early PAR-dependent chromatin remodeling rather than direct interaction with PAR. Moreover, recruitment is not the consequence of reduced molecular crowding at unfolded damaged chromatin but instead originates from facilitated binding to more exposed DNA. These findings are further substantiated by the observation that PAR-dependent chromatin remodeling at DNA lesions underlies increased DNAse hypersensitivity. Finally, the relevance of this new mode of PAR-dependent recruitment to DNA lesions is demonstrated by the observation that reducing the affinity for DNA of both CHD4 and HP1α, two proteins shown to be involved in the DNA-damage response, strongly impairs their recruitment to DNA lesions.

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“…The homeodomain proteins, including CDX2, directly bind to ATM and MRN complex and suppress DNA repair mechanisms by blocking ATM monomerization through MRN complex in HCT-116 cell line [ 42 ]. In cancer cell lines, CDX2 of CRC may serve as a tumor suppressor in DNA damaging environment by interfering DNA damage repair, such as radiation or chemotherapy.…”

Section: Audal-related Homeobox Transcription Factor 2 Plmentioning

confidence: 99%

The role of transcription factor caudal-related homeobox transcription factor 2 in colorectal cancer

Hsu

Yeh

et al. 2020

Tzu Chi Med J

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Colorectal cancer (CRC) is one of the most malignant tumors in humans and causes mass mortality. In the age of precise medicine, more and more subtypes of CRC were classified. The caudal-related homeobox transcription factor 2 (CDX2) is an intestine-specific transcription factor which is implicated in differentiation, proliferation, cell-adhesion, and migration. The loss of CDX2 in immunohistochemical stain was reported to be a prognostic factor of colon cancer, but the clinical application remained controversial. Most of the CRCs expressed or over-expressed CDX2. Homeobox genes can display either an oncogenic or a tumor-suppressing activity. CDX2 regulates the developing intestinal epithelium and CRC by different pathways. The complex regulation of CDX2 and its complex targets cause the difficulties of application for CDX2 in the prediction of prognosis. However, CDX2 is a potential biomarker applied in the precise classification of CRC for personalized medicine. This review partially clarifies the role of CDX2 in CRC.

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Homeodomain Proteins Directly Regulate ATM Kinase Activity

Cited by 7 publications

References 64 publications

ZEB1 is Required for NHEJ-Mediated DSB Repair in Euchromatin

ZEB1 is Required for NHEJ-Mediated DSB Repair in Euchromatin

Poly(ADP-ribose)-dependent chromatin unfolding facilitates the association of DNA-binding proteins with DNA at sites of damage

The role of transcription factor caudal-related homeobox transcription factor 2 in colorectal cancer

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