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Chromatin condensation as a DNA protective response to UV radiation in human melanocytes and aging C. elegans

Award Number: R03AG060202
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Chromatin condensation as a DNA protective response to UV radiation in human melanocytes and aging C. elegans - UV-induced DNA damage is a major cause of age-related skin diseases and photoaging. Although the body can develop defenses over time to UV stress (i.e., melanin concentration and thickening of the stratum corneum), there is a fundamental gap in understanding whether cells can mount an effective immediate protective response to UV. We recently discovered an immediate and robust UV-induced DNA protection mechanism that involves a global chromatin compaction triggered by calcium influx. The chromatin compaction and DNA protection responses were demonstrated in human HeLa cells, and the compaction was also demonstrated in NIH2/4 mouse embryonic fibroblasts and in the roundworm C. elegans. Our long-term goal is to understand the molecular basis of this mechanism, and to investigate if it can be manipulated to increase our natural protection from UV damage. We will explore whether this mechanism declines with age like other stress resistance mechanisms. The objectives of this application are to develop the C. elegans as a model system to probe the age-dependence of this stress resistance mechanism and to use human epidermal melanocytes in combination with C. elegans to gain the first glimpse into the molecular pathway of this UV- induced DNA protective chromatin compaction. The central hypothesis is that chromatin compaction is triggered by a conserved molecular machinery of a photoreceptor acting through the Gαq/11-coupled phototransduction pathway to activate a calcium influx. We hypothesize that this is an evolutionarily conserved response that is less efficient in aged organisms. The rationale for choosing C. elegans is that it is a well- established model system for studying aging with superb genetic and developmental tools. Human primary epidermal melanocytes were chosen because they are human skin cells in which a specific pathway involving photoreceptors and Gαq/11 was shown to control a UV-induced calcium influx. The specific aims for this research are: 1) Test whether UV-induced chromatin compaction protects DNA from further damage in human epidermal melanocytes (HEMs) and in young and old C. elegans. We will UV irradiate HEMs and C. elegans and detect the rate of removal of photoproducts by Southwestern blotting (for HEMs and C. elegans) and in vivo (for C. elegans). 2) Determine whether UVR-induced chromatin compaction involves the Gαq/11-coupled phototransduction pathway and calcium influx in human epidermal melanocytes and C. elegans. This aim will be achieved by RNAi/siRNA knock downs in C. elegans and human primary epidermal melanocytes. The proposed research is innovative because it explores a previously undescribed DNA defense mechanism from UV radiation and it sets as a goal establishing C. elegans as a model system for relating this phenomenon to aging. Adding to our innovative capacity is the ongoing cross-pollination between a C. elegans lab and a mammalian chromatin lab. The results will be significant because new potential targets that control the DNA- protective pathway will be discovered which can lead to better pharmaceutical strategies to protect from UV.


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 = -$2,087 )
2023	2019	TEXAS WOMANS UNIVERSITY	304 ADMINISTRATION DRIVE	DENTON	TX	76204	DENTON	USA	Aging Research	000	2	10/27/2022	NON-COMPETING CONTINUATION	-$4,519
2023	2019	TEXAS WOMANS UNIVERSITY	304 ADMINISTRATION DRIVE	DENTON	TX	76204	DENTON	USA	Aging Research	001	2	5/11/2023	NON-COMPETING CONTINUATION	$2,432
														Subtotal = -$2,087

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	TEXAS WOMAN'S UNIVERSITY	304 ADMINISTRATION DR	DENTON	TX	76204	DENTON	USA	Aging Research	000	2	6/22/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $65,837 )
2019	2019	TEXAS WOMAN'S UNIVERSITY	304 ADMINISTRATION DR	DENTON	TX	76204	DENTON	USA	Aging Research	000	2	5/15/2019	NON-COMPETING CONTINUATION	$65,837
														Subtotal = $65,837

Issue Date FY: 2018 ( Subtotal = $65,527 )
2018	2018	TEXAS WOMAN'S UNIVERSITY	304 ADMINISTRATION DR	DENTON	TX	76204	DENTON	USA	Aging Research	000	1	8/15/2018	NEW	$65,527
														Subtotal = $65,527

Grand Total All Awards = $129,277

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Chromatin condensation as a DNA protective response to UV radiation in human melanocytes and aging C. elegans

Award Number: R03AG060202

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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