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Translational inhibition by Schlafen proteins during the DNA damage response

Award Number: R01GM128155
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Translational inhibition by Schlafen proteins during the DNA damage response - Recently, human Schlafen 11 (SLFN11) - which we had shown to inhibit HIV protein expression due to the distinct codon-usage bias of the virus – was found to determine cell fate after exposure to DNA-damaging agents (DDAs). Cells lacking SLFN11 are resistant to DDAs, but not to other chemotherapeutic drugs. As DDAs are the largest group of cancer drugs, resistance against them impacts a large patient population and thus it is vital to unravel Slfn11's molecular contribution to the efficacy of DDAs, and to restore it in cells w/o Slfn11. So far, the events by which loss of SLFN11 causes resistance to DDAs remained unanswered. We now show that SLFN11 inhibits ATR translation in response to DDAs to enhance cell killing. This discerning inhibition translation is due to the prominent use of specific Leu codons in ATR. SLFN11 inhibits translation when Leu is (frequently) encoded via TTA or CTT, but not when other codons are employed. We demonstrate DDA-induced, SLFN11-mediated cleavage of a distinct tRNA subset including tRNAs Leu-TAA and Leu-AAG. DDA sensitivity in Slfn11-deficient cells can be restored 1) by abrogation of ATR expression; 2) through inhibition of ATR kinase activity; or 3) through the use of Gapmers, a novel technology we adapted to selectively target tRNA Leu-TAA for degradation. We note a novel mechanism of codon-specific regulation of translation by SLFN11 in the DNA damage response exists and provides the first evidence that modulation of a distinct tRNA allows for targeting specific proteins relying on those tRNAs. We provide proof-of-concept that targeting tRNAs by Gapmers is a valid approach to manipulate actions such as cell survival or viral replication. Our overarching goal is to improve our understanding of the function and regulation of Slfn11 during the DNA damage response on a cellular and molecular level. Aim 1 focuses on the analysis of Slfn11 itself, exploring its functional domains and regulation. We already identified several inhibitory phosphorylation sites in Slfn11 implying that dephosphorylation is required for SLFN11 activation, and show that PP1Cγ is the activating phosphatase during the DNA damage response. These findings need to be verified and expanded upon in additional settings (Other cell types and DDAs? Check for possible additional (de)phosphorylation sites? Identify likely cofactors?) The experiments outlined in Aim 2 target the role of the tRNA cleavage (identify cleavage site(s); test potential requirement for post-transcriptional modifications of tRNAs; do cleavage-resistant tRNA Leu-TAA mutants render cells DDA-resistant, and do such “mutants” exist in nature? Possible biological function for the tRNA-derived nucleic acid fragments?). Successful completion of the proposed studies will support the notion that SLFN11-deficient cancer cells can be (re)sensitized to DDA therapy by targeting ATR or distinct tRNAs, and that suppression of specific type II tRNAs might offer a new strategy to overcome resistance to DDAs. Finally, in our HIV studies we found that SLFN11 inhibited the translation of viral proteins during retro/lenti-viral infections, but not other viruses. We now think that the reason for this phenomenon is that retro-viruses cause DNA damage during integration, thereby likely activating SLFN11. In contrast, e.g. Influenza (despite similarity in codon bias to HIV) was not inhibited by SLFN11. We hypothesize now that SLFN11 might actually inhibit Influenza or other “biased” viruses if SLFN11 is independently activated by pharmacological means.


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 = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	7/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $316,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	12/21/2021	NON-COMPETING CONTINUATION	$284,400
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	4	7/26/2022	NON-COMPETING CONTINUATION	$31,600
														Subtotal = $316,000

Issue Date FY: 2021 ( Subtotal = $315,500 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	3	3/19/2021	NON-COMPETING CONTINUATION	$31,550
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	1/29/2021	NON-COMPETING CONTINUATION	$283,950
														Subtotal = $315,500

Issue Date FY: 2020 ( Subtotal = $315,000 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	1/6/2020	NON-COMPETING CONTINUATION	$283,500
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	3/17/2020	NON-COMPETING CONTINUATION	$31,500
														Subtotal = $315,000

Issue Date FY: 2019 ( Subtotal = $314,600 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	2/8/2019	NEW	$314,600
														Subtotal = $314,600

Grand Total All Awards = $1,261,100

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Translational inhibition by Schlafen proteins during the DNA damage response

Award Number: R01GM128155

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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