Roles for MDC1 in cancer development and treatment

Abstract

The DNA damage response (DDR) is necessary to maintain genome integrity and prevent the accumulation of oncogenic mutations. Consequently, proteins involved in the DDR often serve as tumor suppressors, carrying out the crucial task of keeping DNA fidelity intact. Mediator of DNA damage checkpoint 1 (MDC1) is a scaffold protein involved in the early steps of the DDR. MDC1 interacts directly with γ-H2AX, the phosphorylated form of H2AX, a commonly used marker for DNA damage. It then propagates the phosphorylation of H2AX by recruiting ATM kinase. While the function of MDC1 in the DDR has been reviewed previously, its role in cancer has not been reviewed, and numerous studies have recently identified a link between MDC1 and carcinogenesis. This includes MDC1 functioning as a tumor suppressor, with its loss serving as a biomarker for cancer and contributor to drug sensitivity. Studies also indicate that MDC1 operates outside of its traditional role in DDR, and functions as a co-regulator of nuclear receptor transcriptional activity, and that mutations in MDC1 are present in tumors and can also cause germline predisposition to cancer. This review will discuss reports that link MDC1 to cancer and identify MDC1 as an important player in tumor formation, progression, and treatment. We also discuss mechanisms by which MDC1 levels are regulated and how this contributes to tumor formation.

Keywords: Cancer; DNA damage response; DNA damaging agents; MDC1; Transcriptional co-regulator; γ-H2AX.

Figure 1.. MDC1 is a scaffold protein which propagates the phosphorylation of H2AX to form γ-H2AX.

A. DNA double-stranded breaks form free DNA ends. B. Free DNA ends are detected by the MRN complex, which recruits ATM kinase to phosphorylate H2AX to form γ-H2AX. C. MDC1 interacts directly with γ-H2AX to recruit additional MRN complex and ATM, amplifying the γ-H2AX signal. It also recruits RNF8, resulting in the ubiquitination of γ-H2AX. D. In the absence of MDC1, free ends are still detected by the MRN complex, but the γ-H2AX signal is not propagated onto nearby chromatin to form visible γ-H2AX foci.

Figure 2.. Potential model for MDC1-mediated co-activation of AR and ERα.

MDC1 has been shown to co-immunoprecipitate with both AR and ERα, and there is evidence that it plays a role in recruiting GCN5 to acetylate H3K9, resulting in increased transcription of p21 [38, 42].

Figure 3.. MDC1-AS is the antisense transcript of MDC1, and its transcription correlates with MDC1 transcription.

A. Map of MDC1-AS gene relative to MDC1. B. Summary of MDC1 and MDC1-AS RNA expression in benign tissue types. RPKM is reads per kilobase per million mapped reads, a normalized unit of transcription expression. Data from the Human Protein Atlas [89]. C. MDC1 and MDC1-AS levels strongly correlate (r=.992, p<.0001, Pearson correlation).

Figure 4.. Map of MDC1 mutations in human cancer.

MDC1 somatic mutations occur across the entire length of the MDC1 protein, but G1558C, within the PST repeats, is the most common MDC1 mutation observed (Fig. generated in cBioPortal [98, 99]).