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Review
. 2020 Feb 29;43(2):99-106.
doi: 10.14348/molcells.2019.0304.

Role of RUNX Family Transcription Factors in DNA Damage Response

Ann Sanoji Samarakkody  1 , Nah-Young Shin  1 , Alan B Cantor  1   2
Affiliations
Review

Role of RUNX Family Transcription Factors in DNA Damage Response

Ann Sanoji Samarakkody et al. Mol Cells. .

Abstract

Cells are constantly exposed to endogenous and exogenous stresses that can result in DNA damage. In response, they have evolved complex pathways to maintain genomic integrity. RUNX family transcription factors (RUNX1, RUNX2, and RUNX3 in mammals) are master regulators of development and differentiation, and are frequently dysregulated in cancer. A growing body of research also implicates RUNX proteins as regulators of the DNA damage response, often acting in conjunction with the p53 and Fanconi anemia pathways. In this review, we discuss the functional role and mechanisms involved in RUNX factor mediated response to DNA damage and other cellular stresses. We highlight the impact of these new findings on our understanding of cancer predisposition associated with RUNX factor dysregulation and their implications for designing novel approaches to prevent cancer formation in affected individuals.

Keywords: DNA damage response; Fanconi anemia; RUNX1; RUNX2; RUNX3; cancer; cell cycle arrest; p53; tumor suppressor.

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Conflict of interest statement

Disclosure

The authors have no potential conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1. p53-dependent DNA damage response and the Fanconi anemia (FA) pathway.
(A) p53-dependent pathway. DNA damage activates ATR/ATM and CHK1/CHK2 kinases leading to p53 phosphorylation. p53 undergoes p300 dependent acetylation which transactivates specific p53 target genes resulting in either cell cycle arrest and DNA repair or apoptosis. (B) FA pathway. The FA pathway is activated during the S-phase of the cell cycle upon DNA replication fork stalling at ICLs. ATR/CHK1 is activated and in turn activates FA core complex, which promotes the monoubiquitylation of the FANCI-FANCD2 heterodimer. The ubiquitylated FANCD2-FANCI heterodimer at ICLs recruits DNA repair proteins involved in nucleotide excision repair, translesion synthesis and homologous recombination to stabilize the fork and repair ICLs.
Fig. 2
Fig. 2. Role of RUNX proteins in p53-dependent DNA damage response.
In response to DNA damage p53 gets phosphorylated at serine-15 in a phosho-ATM/ATR dependent manner. RUNX1 and RUNX3 play similar roles in promoting p53 acetylation and recruiting it to gene promoters of downstream target genes involved in DNA repair, cell cycle arrest and apoptosis. Association of RUNX2 with HDAC6 dampens acetylation to repress apoptosis and maintain cell cycle progression.
Fig. 3
Fig. 3. Role of RUNX proteins in the FA pathway.
In response to DNA fork stalling at ICLs during the S phase of cell cycle, ATR and PARP1 are activated, which induces RUNX poly(ADP-ribosyl) ation and its interaction with BLM helicase. This leads to efficient recruitment of FANCD2-FANCI onto the ICLs for repair. Data from the article of Tay et al. (2018) (Cell Rep. 24, 1747-1755) in accordance with the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
See this image and copyright information in PMC

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