Nucleotide excision repair efficiency in quiescent human fibroblasts is modulated by circadian clock

Abstract

The efficiency of Nucleotide Excision Repair (NER)process is crucial for maintaining genomic integrity because in many organisms, including humans, it represents the only system able to repair a wide range of DNA damage. The aim of the work was to investigate whether the efficiency of the repair of photoproducts induced by UV-light is affected by the circadian phase at which irradiation occurred. NER activity has been analyzed in human quiescent fibroblasts (in the absence of the cell cycle effect), in which circadian rhythmicity has been synchronized with a pulse of dexamethasone. Our results demonstrate that both DNA damage induction and repair efficiency are strictly dependent on the phase of the circadian rhythm at which the cells are UV-exposed. Furthermore, the differences observed between fibroblasts irradiated at different circadian times (CTs) are abolished when the clock is obliterated. In addition, we observe that chromatin structure is regulated by circadian rhythmicity. Maximal chromatin relaxation occurred at the same CT when photoproduct formation and removal were highest. Our data suggest that the circadian clock regulates both the DNA sensitivity to UV damage and the efficiency of NER by controlling chromatin condensation mainly through histone acetylation.

The circadian coordination of cell biology

“…Nucleotide excision repair (NER) responds to single-strand DNA damage and UV-induced DNA adducts. Both the activity and efficiency of this repair pathway exhibits circadian rhythmicity ( Kang et al, 2009 ), as do the protein levels of a key coordinator of NER, xeroderma pigmentosum A ( Kang et al, 2010 ; Bee et al, 2015 ). Three different repair pathways target DNA double-stranded breaks.…”

G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes

“…To this end, it is unsurprising that clock gene factors can control and integrate metabolic sensation, day-to-day age assessment and DNA stability. Thus, components of circadian clock, such as Aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1-CLOCK), period circadian protein homolog 1 (PER1), period circadian protein homolog 2 (PER2), period circadian protein homolog 3 (PER3) and inactive tyrosine-protein kinase transmembrane receptor ROR (ROR1), are suggested to be involved in cellular response to genotoxic stress [ 72 , 86 , 87 , 88 , 89 ]. As cellular clocks not only regulate chronological aging, but also the rate/extent of metabolic dysfunction, telomere stability and DNA damage [ 90 , 91 , 92 ], it is unsurprising that clock functionality is now linked to many age-related disorders, e.g., dementia [ 93 , 94 ], glycemic/adiposity disorders [ 95 ] and premature aging diseases associated with attenuated DDR [ 65 , 66 , 67 , 68 , 69 , 70 , 96 , 97 ].…”

Genetic mechanisms of the influence of light and phototransduction on Drosophila melanogaster lifespan

“…Принимая во внимание работы, обнаруживающие сни жение риска смерти от различных причин при утрате зрения (Lehrer, 1981) и врожденной слепоте (Анисимов и др., 2013), можно предположить, что усиление фоторезистентности посредством снижения с возрастом экспрессии генов, кодирующих фоторецепторы и фототрансдукторы, является генетически детерминированной адаптацией к повреждающим стимулам фоторежима, возникшей еще на ранних этапах эволюции, когда живые организмы экспонировались не в пример большим до зам оптического и космического излучений, нежели мы можем зарегистрировать в настоящее время. Тесная связь элементов центрального осциллятора клетки и фотолиаз, фотореактивационные свойства некоторых криптохромов, а также способность элементов осциллятора участвовать в контроле клеточного цикла (Feillet et al, 2015) и репарации ДНК (Bee et al, 2015;Papp et al, 2015) служат подтверждениями нашего предположения о сопряженности механизмов фототрансдукции и контроля продолжительности жизни (Patel et al, 2016).…”