Sunday, November 24, 2024
11/24/2024
The Coats plus syndrome is a rare and life-threatening genetic disorder characterized by multi-system developmental defects that lead to bilateral exudative retinopathy, retinal telangiectasias, growth retardation, intracranial calcifications, bone abnormalities, gastrointestinal vascular ectasias, and common early-aging pathological features. Like many other developmental disorders, Coats plus is caused by defects in genes involved in maintaining global genome integrity. Specifically, it is caused by loss-of-function mutations in the human CTC1/STN1/TEN1 (CST) complex, which is a trimeric complex that preferentially binds to G-rich ssDNA or ss-ds DNA junctions and is critical for preventing genome instabilities arising from replication perturbation. We hope to aid in better understanding of disease development and designing of effective therapeutic strategies by investigating the mechanisms governing genome stability under replication stress. In response to fork stalling, signaling cascades activate multiple pathways including fork reversal, translesion synthesis, repriming downstream of stalled sites, and dormant origin firing to rescue stalled replication. Activities of these pathways need to be tightly regulated to ensure replication fidelity. The objectives of this proposal is to delineate a novel signaling pathway in response to replication stress, elucidate how it regulates protein interplays and recruitment at stalled forks, and understand the mechanism regulating the repriming pathway. In Aim 1, we hypothesize that a calcium-dependent signaling pathway phosphorylates STN1 to activate CST at stalled forks to protect the stability of stalled forks. We will elucidate this new signaling pathway and determine how this pathway antagonizes unscheduled nascent strand DNA degradation and regulates fork protection. In Aim 2, we will investigate how this signaling pathway regulates the interplay of single-strand DNA binding proteins at forks and other fork binding proteins. In Aim 3, we will investigate the mechanism for restricting excessive repriming to prevent ssDNA gap formation and genome instability. We will combine highly sensitive cell-based analyses, single-molecule and powerful biochemical assays to accomplish the goals of the proposed research. We expect that our efforts will identify new factors and pathways regulating the rescue of stalled replication and the preservation of genome stability.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
