Date: July 07, 2021
Time: 8:00am (PDT), 11:00am (EDT)
The DNA damage response is extremely crucial in maintaining genomic integrity. Failure to repair damaged DNA can result in the propagation of mutations and lesions that can contribute to tumorigenesis. The poly [ADP-ribose] polymerase (PARP), is a DNA damage response protein that is transiently recruited to sites of DNA breaks, and is involved in the signaling and recruitment of other important DNA damage response proteins. PARP is involved in the regulation of the chromatin remodeling enzyme, Amplified in Liver Cancer 1 (ALC1). ALC1 functions as a chromatin remodeler, and studies from our laboratory has shown that ALC1 interacts with the E3 ubiquitin-protein ligase, Tripartite Motif-containing 33 (TRIM33) during DDR. TRIM33 has been known to play a role in numerous biological process such as tumorigenesis, TGF-B signaling and transcriptional regulation. We have observed that TRIM33 is recruited to sites of DNA breaks after the activation of PARP, and interacts with ALC1. TRIM33-deficient cells have shown to exhibit sensitivity to DNA damage, with the subsequent and prolonged retention of ALC1 at the sites of DNA breaks. Prolonged chromatin relaxation facilitated by ALC1 leads to increased sensitivity to DNA damaging agents. This sensitivity can be overcome with the overexpression of TRIM33. Our laboratory has demonstrated that TRIM33 regulates the activity of ALC1 during DNA repair by facilitating the timely removal of ALC1 at the sites of DNA breaks, thus promoting efficient DNA repair. There is current research focus that aims to investigate the dynamics of TRIM33 and ALC1, and their interactions with other key proteins involved in DNA repair, especially those proteins that are differentially regulated.
- Describe and understand the mechanisms of DNA Repair
- Discuss how the PARP dependent DNA damage response pathway is regulated
- Discuss and understand how key proteins involved in DDR including TRIM33 and ALC1 can serve as actionable targets in the treatment of certain cancer
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