Monday, September 9, 2024 9/9/2024

Evaluating the mechanism by which the DYNLL1-MRE11 complex regulates DNA end resection and genome stability.

Award Number: F32GM149115
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY The synthetic lethal interaction of BRCA deficiency with PARPi is being exploited therapeutically in diverse clinical contexts, including ovarian, pancreatic, and prostate cancers). However, PARPi resistance has emerged as a vexing clinical problem for the treatment of BRCA1/2-deficient ovarian cancer carcinomas. Analyses of PARPi resistance in BRCA1-mutant tumors across independent studies suggest that loss of genes involved in either promoting NHEJ or suppressing HR leads to the partial restoration of HR in the absence of BRCA1 activity. 53BP1 emerged as the master regulator that brings multiple complexes to the DSB. Loss of any of these factors causes PARPi resistance in BRCA1 mutant cells. Therefore, further understanding of factors that regulate the processing of DNA ends that are crucial for pathway choice have tremendous relevance in cancer biology. Our lab has previously identified that in ovarian cancer cells, loss of DYNLL1, a factor that is constitutively bound to 53BP1, also results in enhanced HR and PARPi resistance. We found that DYNLL1pS88 directly binds to and inhibits MRE11, thereby blocking the initiation of DNA end resection. However, how the interaction of DYNLL1 with MRE11 impairs its nuclease activity or its recruitment to foci remains unexplored. Furthermore, how this interaction is regulated in the context of the DNA damage response, for example, which kinase/phosphatase(s) regulates the phosphorylation of S88 residue of DYNLL1 to modulate its interaction with MRE11 needs to be investigated. Our overall objectives in this application are to identify the molecular mechanism(s) regulating repair pathway choice by further understanding how end resection proteins are regulated. Our central hypothesis is that cell cycle-specific regulation of DYNLL1 promotes BRCA1/BARD1 mediated ubiquitination of MRE11, thereby facilitating end resection at DSBs in S phase. We aim to understand the mechanism by which DYNLL1 mediates end resection and HR. We will first investigate the dynamics between BRCA1 and DNA-PKcs and how it regulates the DYNLL1 and MRE11 activity in the context of the cell cycle. Investigating the dynamics of these end resecting factors and their regulation in DSB repair bear significant clinical relevance in combating PARPi resistance in BRCA1-mutant tumors. Therefore, we propose to determine whether alterations in mechanisms involved in attenuated DNA end resection may drive development of PARPi resistance in the high grade serous ovarian cancer (HGSOC) using patient derived xenografts (PDXs) and primary tumors. We expect that these studies will further our understanding of how end resection machinery is regulated to ensure that the appropriate repair pathway is activated. Further understanding of these end resection factors and how they are dysregulated in cancer may lead us to a relevant therapeutic target to combat PARPi resistant cancers.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $74,284 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	2	1/22/2024	NON-COMPETING CONTINUATION	$69,500
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	001	2	5/24/2024	NON-COMPETING CONTINUATION	$4,784
														Subtotal = $74,284

Issue Date FY: 2023 ( Subtotal = $69,080 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	1/12/2023	NEW	$67,174
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	1	2/8/2023	NEW	$0
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	1	2/9/2023	NEW	$1,906
														Subtotal = $69,080

Grand Total All Awards = $143,364

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Evaluating the mechanism by which the DYNLL1-MRE11 complex regulates DNA end resection and genome stability.

Award Number: F32GM149115

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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