CLOCK'S DIFFERENTIAL TRANSCRIPTONAL CONTROL ON OGG1 AND APE1 CIRCADIAN EXPRESSION

CASTRO-PASCUAL, I; DAS NEVES OLIVEIRA, A; MELENDEZ, M; CARGNELLUTTI E; ALTAMIRANO FG; FERRAMOLA, M.; LACOSTE MG; DELGADO SM; ANZULOVICH AC

MENDOZA

Congreso; SBCuyo 2022; 2022

The circadian clock integrates external environmental changes with internal physiology. Different studies have describeda role of clock molecular machinery in the regulation of DNA repair mechanisms. In this sense, other authors reported aclock-controlled modulation of DNA nucleotide excision repair. Accordingly, we previously reported evidence ofcircadian rhythmicity in the expression of genes involved in the DNA base excision repair (BER) system in 22-montholdrats. BER is a key mechanism to avoid oxidative and alkylative DNA damage, which predisposes to different diseasessuch as cancer or neurodegenerative disorders. Our objective was to elucidate the molecular mechanisms involved in thecontrol of the circadian expression of the enzymes involved in the BER system. Through in vitro transient transfectionstudies in NIH-3T3 cells, we assayed the response of the regulatory regions of Ogg1 and Ape1 genes to deBMAL1:CLOCK heterodimer. Previously, our bioinformatics studies revealed 13 E-box-like (CANNTG) and 5 perfect(CACGTG) E-box sites in regulatory regions of Ogg1 and Ape1, respectively. Subsequently, the bioluminescence assaysshowed that the BMAL1:CLOCK heterodimer exerted a differential regulation, activating the Luc expression driven bythe regulatory region of Ogg1 (P < 0.001), and repressing the Luc expression driven by the regulatory region of Ape1 (P< 0.01). The ability to anticipate and repair cyclical DNA damage is essential for the protective functions of tissues,especially during aging; thus, our results would contribute to the growing evidence that circadian clocks may regulate thecellular response to DNA damage.