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Principal Investigator: Shobhan Gaddameedhi
Organization: NORTH CAROLINA STATE UNIVERSITY RALEIGH
Fiscal Year: 2024
Award: $367,565
Funding agency: National Institute of Environmental Health Sciences
Circadian clock disruption: A risk factor for environmental carcinogenesis
Abstract/Summary
Circadian clocks respond to environmental time cues to coordinate 24-hour rhythmicity in gene
expression and biological processes in virtually all cells of the body. According to the US Department of Labor,
~15-20% of Americans are engaged in rotating shift work, and the resulting altered timing of wake/sleep
disrupts their endogenous circadian clock. Epidemiological studies have concluded that individuals who
perform long-term rotating shift work suffer from an increased risk of several cancer types, including skin
cancers. Skin cancer is the most common malignancy and its incidence is increasing dramatically in the U.S.
Among the contributing factors, exposure to solar ultraviolet B (UVB) radiation is the major risk factor (up to
90%) for malignant transformation of skin cells and skin cancer development. In humans and mice, nucleotide
excision repair (NER) removes genetic damage caused by UVB. Therefore, protection from UVB exposure and
ensuring efficient NER capacity are critical for maintenance of genomic stability and prevention of skin cancer.
Previous studies using genetic mouse models have shown that the circadian clock regulates several tumor
suppressing pathways, including NER, that are critical for preserving genomic stability and protection against
environmental carcinogenesis. However, there is a fundamental gap in understanding how circadian disruption
associated with rotating shift work leads to environmental carcinogenesis and in the underlying molecular
mechanisms that influence disease progression in humans. This lack of knowledge is an important roadblock
because it highlights the need for mechanistic insight into malignant transformation and represents a barrier to
predicting the severity of disease outcomes in shift workers. The overall objectives of this project are to identify
and characterize early stage carcinogenesis mechanisms and consequences of circadian disruption in UVB-
induced skin carcinogenesis. Our central hypothesis, supported by preliminary data, is that circadian disruption
undermines DNA repair capacity, inflammatory responses, and other genotoxic stress-related cellular
pathways that underlie the carcinogenicity of shift work. Our studies use circadian synchronized skin cells in
vitro, circadian-disrupted and skin carcinogenesis-prone SKH-1 genetic mouse models in vivo, and skin
samples from human subjects in vivo. In Aim 1, we will determine how the circadian rhythm impacts solar UVB
radiation-mediated DNA damage responses including DNA repair and inflammatory responses. The
experiments described in Aim 2 will examine how clock disruption by rotating shift work influences circadian
rhythmicity and NER. In Aim 3, we will characterize how rotating shift work and genetic disruption of the
circadian clock influence skin cancer initiation and progression. Collectively, the outcomes from these studies
will provide a molecular roadmap of circadian disruption in UVB radiation-mediated genomic instability and
carcinogenesis and will lead to the identification of novel mechanisms that can be applied toward disease
prevention in individuals with abnormal circadian function.
Terms: <Acute><Address><Affect><American><Beta Particle><Beta Radiation><Beta Rays><Biological Function><Biological Process><Cancer Causing Agents><Cancer Induction><Cancers><Carcinogenesis Mechanism><Carcinogens><Cell Body><Cell Communication and Signaling><Cell Cycle Checkpoint><Cell Signaling><Cells><Charged Particles-Electrons Radiation><Chronic><Circadian Dysregulation><Circadian Rhythms><Critical Paths><Critical Pathways><Cues><Cutaneous Disorder><Cyclicity><DNA Damage><DNA Damage Repair><DNA Injury><DNA Repair><Data><Dermatoses><Development><Disease><Disease Outcome><Disease Progression><Disorder><Ecological impact><Ensure><Environmental Factor><Environmental Impact><Environmental Risk Factor><Environmental genotoxicant><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Event><Experimental Models><Exposure to><Fibroblasts><Frequencies><Gene Expression><Genes><Genetic><Genome><Genome Instability><Genome Stability><Genomic Instability><Genomic Stability><Genotoxic Stress><HRS Mouse><Hairless Mice><Health><Hour><Human><Impairment><In Vitro><Inbred HRS Mice><Incidence><Individual><Induced DNA Alteration><Induced Mutation><Induced Sequence Alteration><Inflammation><Inflammatory><Inflammatory Response><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Light><MMH Gene><MUTM Gene><Maintenance><Malignant><Malignant - descriptor><Malignant Neoplasms><Malignant Skin Neoplasm><Malignant Tumor><Mediating><Mice><Mice Mammals><Mission><Modern Man><Molecular><Murine><Mus><N-Glycosylase/DNA Lyase Gene><NIEHS><National Institute of Environmental Health Sciences><Nucleotide Excision Repair><Nyctohemeral Rhythm><OGG1><OGG1 gene><OGH1 Gene><Observational epidemiology><Oncogens><Outcome><Outcome Study><Pathway interactions><Periodicity><Phase><Photoradiation><Predisposition><Prevent skin cancer><Preventative intervention><Preventative strategy><Prevention><Prevention strategy><Preventive strategy><Process><Punch Biopsy><Regulation><Research><Rhythmicity><Risk><Risk Factors><Role><Rotation><Sampling><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Skin Cancer><Skin Carcinogenesis><Skin Diseases><Skin Diseases and Manifestations><Skin Neoplasms><Skin Tumor><Sleep disturbances><Study models><Susceptibility><Testing><Time><Twenty-Four Hour Rhythm><U.V. protection><UV protection><UVB><UVB induced><UVB radiation><Ultraviolet B><Ultraviolet B Radiation><Unscheduled DNA Synthesis><Work><XPA><XPA Complementing Gene><XPA gene><XPAC><aberrant sleep><biological signal transduction><cancer initiation><cancer progression><cancer risk><cancer type><carcinogenesis><carcinogenicity><cell cycle check point><circadian><circadian abnormality><circadian clock><circadian disruption><circadian disturbance><circadian dysfunction><circadian impairment><circadian pacemaker><circadian process><cutaneous carcinogenesis><cutaneous disease><daily biorhythm><day shift><dermal disease><dermal disorder><developmental><disease prevention><disease severity><disorder prevention><disrupted sleep><disturbed sleep><environmental carcinogenesis><environmental mutagenesis><environmental mutagens><environmental risk><epidemiologic investigation><epidemiology study><experiment><experimental research><experimental study><experiments><human subject><impaired sleep><improved><in vivo><in vivo Model><insight><intervention for prevention><interventional strategy><irregular sleep><life-style factor><lifestyle factors><malignancy><malignant skin tumor><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><night shift><night work><novel><oncogenic agent><pathway><patient population><preservation><prevention intervention><preventional intervention strategy><preventive intervention><response><shift work><shiftwork><skin cancer prevention><skin disorder><sleep disruption><sleep dysregulation><social role><solar UV><solar ultraviolet radiation><tumor><tumor progression><ultra violet B radiation><ultraviolet B induced><ultraviolet b radiation induced><ultraviolet light b induced><ultraviolet protection><virtual><β-Particle><β-Rays>