Document text
Principal Investigator: Roderick O'Sullivan
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $349,752
Funding agency: National Cancer Institute
ABSTRACT
Cancer cells must activate a telomere elongation mechanism and acquire genomic alterations to survive. Many
of the most lethal cancers rely on the Alternative Lengthening of Telomeres (ALT) telomere elongation pathway.
ALT is strongly associated with recurrent mutations in genes encoding chromatin modifiers such as the ATRX-
DAXX chromatin remodeling/histone deposition complex. These disrupt the assembly of telomeric chromatin,
provoking replicative stress and double-strand breaks (DSBs) that stimulate specialized homology-directed DNA
repair (HDR) mechanisms to repair and extend telomeres. Thus, the ALT pathway represents a valuable target
for cancer therapy development. Despite significant advances in understanding these unique ALT-associated
HDR (ALT-HDR) mechanisms, the ALT pathway remains unexploited for cancer therapy development.
The mono-ADP-ribosylation (MARylation) of chromatin has recently emerged as a key sensor and
initiator of the DNA damage response. MARylation predominantly occurs on serine residues and relies on HPF1,
which interacts with PARP1. MARylation of specific serines on histones seeds further PARylation that
destabilizes nucleosomes proximal to DNA double strand breaks (DSBs) and licenses the recruitment of the first
wave of DNA repair complexes. ARH3 is the only known enzyme capable of removing MAR synthesized by the
HPF1-PARP1 complex. Despite biochemical evidence supporting its fundamental role in genome maintenance,
the identity of additional cellular targets of serine MARylation, and effects of its deregulation, remain obscure. In
Aim 1 we will assess the impact of ARH3 and HPF1 disruption on ALT-HDR mechanisms and survival of ALT
cancer cells. In Aim 2, we will employ novel approach to track histones as they are being deposited at telomeres
and evaluate the impact that this has on transcription of TERRA and the recruitment of major mediators of ALT.
We will also employ innovative proteomics to identify telomeric targets of MARylation. The successful completion
of these aims will contribute to the understanding of this important chromatin mark during ALT-HDR and its
impact on cancer cell survival.
Terms: <ADP Ribose><ADP ribosylation><ATRX><ATRX gene><Address><Adenosine 5'-(trihydrogen diphosphate), P'-5-ester with D-ribose><Adenosine 5'-(trihydrogen diphosphate), P'-5-ester with D-ribose, homopolymer><Adenosine 5'-Diphosphoribose><Adenosine Diphosphate Ribose><Adenosine Diphosphoribose><Affect><Assay><Autoregulation><BING2><Bioassay><Biochemical><Biological Assay><Bypass><Cancer Cause><Cancer Etiology><Cancer Treatment><Cancerous><Cancers><Cell Body><Cell Survival><Cell Viability><Cell division><Cells><Chaperone><Chromatin><Chromatin Assembly><Chromatin Modeling><Chromatin Remodeling Complex><Chromatin Remodeling Factor><Chromosomes><Complex><DAXX><DAXX gene><DNA><DNA Alteration><DNA Damage><DNA Damage Repair><DNA Double Strand Break><DNA Injury><DNA Repair><DNA Replication><DNA Sequence Alteration><DNA Synthesis><DNA biosynthesis><DNA mutation><Death Associated Protein 6><Deoxyribonucleic Acid><Deposit><Deposition><Detection><Disease><Disorder><Dissection><Ensure><Enzyme Gene><Enzymes><Functional RNA><Gene Transcription><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genetic mutation><Genome><Glycohydrolases><Glycosidases><Glycoside Hydrolases><Goals><Histone H3.3><Histones><Homeostasis><Impairment><Individual><Intermediary Metabolism><Knowledge><L-Serine><Length><Licensing><Maintenance><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Measures><Mediator><Metabolic Processes><Metabolism><Molecular><Molecular Chaperones><Mutate><Mutation><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleosomes><Optics><Pathway interactions><Patients><Phase><Physiological Homeostasis><Poly Adenosine Diphosphate Ribose><Poly-ADPR><Process><Prognosis><Proteomics><RNA Expression><Recurrence><Recurrent><Regulation><Repair Complex><Repression><Research><Role><Sequence Alteration><Serine><Stress><Structure><Telomere Maintenance><Telomere Pathway><Telomeres, Telomerase, Cellular Aging, and Immortality><Transcription><Unscheduled DNA Synthesis><Untranslated RNA><alpha thalassemia mental retardation X-linked gene><anti-cancer therapy><cancer cell><cancer prevention><cancer therapy><cancer-directed therapy><cellular targeting><chromatin modification><chromatin modifier><chromatin remodeling><defined contribution><develop therapy><genome mutation><genomic alteration><histone modification><improved><innovate><innovation><innovative><intervention development><malignancy><mutant><neoplasm/cancer><new approaches><noncoding><novel approaches><novel strategies><novel strategy><optical><pathway><poly (ADP-ribose)><poly ADP ribose glycohydrolase inhibitor><poly ADPR glycohydrolase inhib><preservation><public health relevance><recruit><repair><repaired><response><sensor><social role><synergism><targeted cancer therapy><telomere><therapeutic target><therapy development><treatment development><α-thalassemia mental retardation X-linked gene>