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HORMAD1 directs the assembly of a meiotic-Shieldin complex in meiosis and cancer

Award Number: F32CA239339
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/16/2019
PERIOD OF PERFORMANCE END DATE: 06/18/2021

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HORMAD1 directs the assembly of a meiotic-Shieldin complex in meiosis and cancer - PROJECT SUMMARY Timely and regulated repair of broken DNA is a crucial barrier to cancer formation. My sponsor laboratory has recently discovered and characterized the Shieldin (SHLD) protein complex, a novel regulator of repair which plays a crucial role in determining whether DNA double-strand breaks (DSB) are repaired by homologous recombination (HR) or non-homologous end joining (NHEJ), the two major cellular pathways of DSB repair. SHLD acts by directly inhibiting HR, thereby pushing the balance of DSB repair toward the mutagenic NHEJ pathway in specific contexts where it has been recruited by the chromatin binding proteins 53BP1 and RIF1. However, my preliminary data suggests that SHLD may be ‘hijacked’ by inappropriate expression of the normally meiosis-specific gene HORMAD1, leading to an unrestricted and mutagenic inhibition of recombination outside of normal SHLD-recruiting chromatin domains. HORMAD1 expression is aberrantly activated in up to 5% of breast cancers (METABRIC) and enforces a BRCA1-mutant-like state of recombination deficiency and sensitivity to pharmacological PARP inhibitors (PARPi); HORMAD1 expression may therefore also be a useful biomarker for cancers that are sensitive to the clinically approved PARPi olaparib. Interestingly, one of the previously described roles of HORMAD1 in meiosis is to inhibit undesirable recombination events between sister chromatids. It is therefore likely that my studies of a HORMAD1-SHLD complex in cancer will also provide insights into essential regulatory mechanisms at work during meiotic recombination. The specific aims of this project are thus to: 1) characterize the composition and regulation of HORMAD1-containing SHLD (mSHLD) complexes in mitotically dividing cancer cells and, 2) study the contribution of mSHLD to the regulation of meiotic recombination and gametogenesis in newly-generated mouse models. This strategy will necessitate the acquisition of technical and theoretical skills that will be of significant benefit in supporting my independent career, including experience with a new model system (mice) and a new field of study (meiotic recombination). Importantly, my sponsor laboratories balance these requirements with the training, expertise, mentorship, collaborators and institutional support that ensures extensive career development during the training period. In the short-term, this will result in significant insights into a novel source of genome instability that may be both a clinically useful biomarker and an important contributor to human fertility. In the long-term, these findings and the skills acquired in making them may also provide the foundation of my independent career.


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: 2023 ( Subtotal = -$4,511 )
2023	2020	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD				GBR	Cancer Research Manpower	000	2	11/23/2022	NON-COMPETING CONTINUATION	-$4,510
2023	2020	REDACTED DUE TO PII		OXFORD				GBR	Cancer Research Manpower	001	2	12/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = -$4,511

Issue Date FY: 2021 ( Subtotal = -$13,885 )
2021	2020	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE			GBR	Cancer Research Manpower	002	2	8/16/2021	NON-COMPETING CONTINUATION	$0
2021	2020	REDACTED DUE TO PII		OXFORD	OXFORDSHIRE			GBR	Cancer Research Manpower	001	2	8/11/2021	NON-COMPETING CONTINUATION	-$13,885
2021	2020	REDACTED DUE TO PII		OXFORD	OXFORDSHIRE			GBR	Cancer Research Manpower	000	2	11/13/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = -$13,885

Issue Date FY: 2020 ( Subtotal = $69,306 )
2020	2020	REDACTED DUE TO PII		OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Cancer Research Manpower	002	2	9/10/2020	NON-COMPETING CONTINUATION	-$7,098
2020	2020	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Cancer Research Manpower	001	2	9/1/2020	NON-COMPETING CONTINUATION	$11,850
2020	2020	REDACTED DUE TO PII		OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Cancer Research Manpower	000	2	8/31/2020	NON-COMPETING CONTINUATION	$64,554
														Subtotal = $69,306

Issue Date FY: 2019 ( Subtotal = $63,746 )
2019	2019	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Cancer Research Manpower	005	1	8/27/2019	NEW	$0
2019	2019	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Cancer Research Manpower	002	1	3/20/2019	NEW	$10,850
2019	2019	REDACTED DUE TO PII		OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Cancer Research Manpower	004	1	8/27/2019	NEW	$0
2019	2019	REDACTED DUE TO PII		OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Cancer Research Manpower	000	1	3/19/2019	NEW	$52,896
2019	2019	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Cancer Research Manpower	003	1	3/20/2019	NEW	$0
2019	2019	REDACTED DUE TO PII		OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Cancer Research Manpower	001	1	3/19/2019	NEW	$0
														Subtotal = $63,746

Grand Total All Awards = $114,656

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HORMAD1 directs the assembly of a meiotic-Shieldin complex in meiosis and cancer

Award Number: F32CA239339

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/16/2019

PERIOD OF PERFORMANCE END DATE: 06/18/2021

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