Saturday, May 10, 2025
5/10/2025
Co-Regulation of Alternative Lengthening of Telomeres and Chromatin Dynamics in ATRX-DAXX deficient cancer cells - Abstract Cancer cells must activate a telomere elongation mechanism and acquire genomic alterations. Many of the most lethal cancers rely on the Alternative Lengthening of Telomeres (ALT) pathway. ALT is a specialized homology directed repair (HDR) mechanism dedicated to repair and elongate telomeres, thereby ensuring the proliferative immortality of these cancer cells. Recurrent inactivating missense mutations in genes encoding the ATRX-DAXX chromatin remodeling/histone H3.3 deposition complex exhibit a strong concordance with tumors in which ALT is activated, with both arising late in metastatic disease. These loss of function mutations disrupt ATRX-DAXX mediated assembly of chromatin, provoking replicative stress and double-strand breaks (DSBs) within telomeres that is believed to stimulate ALT-associated HDR. Whereas the HDR mechanisms that underpin ALT have been extensively studied, the mechanisms governing how cells compensate for loss of ATRX-DAXX to maintain chromatin while also acquiring metastatic traits remain ill-defined. This proposal builds on our recent report that upon inactivation of ATRX-DAXX, a related chromatin assembly factor known as HIRA becomes indispensable for de novo histone H3.3 deposition and telomere extension in ALT cancer cells. Furthermore, we discovered that the depletion of HIRA provoked acute systemic death of ATRX-DAXX deficient cells. Strikingly, this cytotoxicity was reversed by reconstitution of ALT cells with wild type ATRX protein. These data provided compelling evidence for a compensatory function adopted by HIRA due to ATRX-DAXX deficiency that could be harnessed to eliminate ALT cancer cells.
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).