Investigation of the mechanistic role of TLKs in Nucleotide Excision Repair

The genome is constantly bombarded with endogenous and exogenous sources of DNA damage. To protect the integrity of the genome under such conditions the DNA damage response pathways have evolved to rapidly respond to these events by recognizing damage has occurred then either repairing the damage or triggering cell death to prevent the propagation of the damaged DNA. Cells that have dysfunctional DNA damage response pathways are prone to transformation and can lead to carcinogenesis, as illustrated by hereditary cancer syndromes. A typical DNA damage response involves the coordination of a complex suite of proteins with scaffolding and/or enzymatic functions. Our previous work has identified a novel role for the Tousled-Like Kinases (TLK1 and 2) within the DNA damage response. These serine/threonine kinases regulate their protein-protein interactions through autophosphorylation of their N-termini. We will study how this autophosphorylation is regulated by purification of each kinase and performing biochemical and biophysical in-vitro assays. This study will also elucidate the DNA damage response pathways that recruit TLKs to damaged chromatin and what that recruitment accomplishes. The proposed research will fill the knowledge gaps in how TLK autophosphorylation is regulated and what events control this regulation to permit TLK function at sites of DNA damage. The long-term goal of this research is to identify the mechanistic regulation of TLKs and potentially identify novel chemotherapeutic targets and provide better outcomes for cancer patients. Project Number: 5P20GM152281-03 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Kirk West | Institution: UNIV OF ARKANSAS FOR MED SCIS, LITTLE ROCK, AR | Award Amount: $282,454 | Activity Code: P20 | Study Section: ZGM1-RCB-3(C1) View on NIH RePORTER: https://reporter.nih.gov/project-details/11469596