Pre-steady-state kinetic and mutational insights into mechanisms of endo- and exonuclease DNA processing by mutant forms of human AP endonuclease

Aperçu cinétique et mutationnel à l'état pré-établi des mécanismes de traitement de l'ADN par les endo- et exonucléases par des formes mutantes de l'endonucléase AP humaine.

Artemiy Bakman (1) , Alexander Ishchenko (2) , Murat Saparbaev (2) , Olga Fedorova (1) , Nikita Kuznetsov (1)

1 ICBFM SB RAS - Institute of Chemical Biology and Fundamental Medicine [Novosibirsk, Russia]
2 IGC - Instabilité du génome et cancer

It was proposed that the last universal common ancestor (LUCA) evolved under high temperatures in an oxygen-free environment, similar to those found in deep-sea vents and on volcanic slopes. Therefore, spontaneous DNA decay, such as base loss and cytosine deamination, was the major factor affecting LUCA’s genome integrity. Cosmic radiation due to Earth’s weak magnetic field and alkylating metabolic radicals added to these threats. Here, we propose that ancient forms of life had only two distinct repair mechanisms: versatile apurinic/apyrimidinic (AP) endonucleases to cope with both AP sites and deaminated residues, and enzymes catalyzing the direct reversal of UV and alkylation damage. The absence of uracil–DNA N-glycosylases in some Archaea, together with the presence of an AP endonuclease, which can cleave uracil-containing DNA, suggests that the AP endonuclease-initiated nucleotide incision repair (NIR) pathway evolved independently from DNA glycosylase-mediated base excision repair. NIR may be a relic that appeared in an early thermophilic ancestor to counteract spontaneous DNA damage. We hypothesize that a rise in the oxygen level in the Earth’s atmosphere ~2 Ga triggered the narrow specialization of AP endonucleases and DNA glycosylases to cope efficiently with a widened array of oxidative base damage and complex DNA lesions.

Domaines: Sciences du Vivant [q-bio]

Artemiy Bakman, Alexander Ishchenko, Murat Saparbaev, Olga Fedorova, Nikita Kuznetsov. Pre-steady-state kinetic and mutational insights into mechanisms of endo- and exonuclease DNA processing by mutant forms of human AP endonuclease. Biochimica et Biophysica Acta (BBA) - General Subjects, 2022, 1866 (12), pp.130198. ⟨10.1016/j.bbagen.2022.130198⟩. ⟨hal-03858673⟩