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  • The study of TcMYH protein is

    2022-06-16

    The study of TcMYH protein is a step forward for the characterization of a GO system in T. cruzi. The complete system appears to be present and our findings demonstrate that is important to maintain DNA stability of the nuclear and mitochondrial genomes, particularly in the presence of oxidative stress (Furtado et al., 2012, Aguiar et al., 2013).
    Conclusions The data presented in this work indicates that Trypanosoma cruzi has a functional MYH DNA glycosylase, which participates in nuclear and mitochondrial DNA Base Excision Repair mechanisms of this parasite.
    Conflict of interest
    Introduction: MutY's Nobel Heritage In the late 1980s, the laboratory of 2015 Chemistry Nobel Laureate Paul Modrich discovered an activity in E. coli that was able to restore G:A mismatches to G:C base-pairs [1]. This activity was independent of methylation status of the template strand, and therefore could not be attributed to mismatch repair (MMR). Around the same time, Miller and co-workers identified a mutator locus in E. coli (Ec) that generates G:C to T:A transversion mutations, which they termed as the mutY gene [2]. Together Miller and Modrich determined that the mutY gene product was an LY2157299 receptor glycosylase [3], similar to the base excision repair (BER) Uracil-DNA glycosylase (UDG) [4], discovered by 2015 Chemistry Nobel Laureate Tomas Lindahl [5]. Using a combination of biochemistry and genetics, Miller, Michaels and co-workers demonstrated that MutY plays an important role in the prevention of mutations caused by the oxidatively damaged guanine lesion, 8-oxo-7,8-dihydroguanine (8-oxoG) by removing adenine (A) from 8-oxoG:A base pairs that form due to the miscoding properties of 8-oxoG [2], [6], [7], [8], [9], [10]. The knowledge of these fundamental features of MutY were crucial in the discovery of a colorectal cancer (CRC) predisposition syndrome involving variants of the human MutY homolog, MUTYH, in a disease referred to as MUTYH-associated polyposis (MAP) [11], [12]. The importance of MUTYH in MAP, and increased interest in targeting DNA repair enzymes as new therapeutic strategies, have upped the ante in understanding the inherent chemistry of MutY/MUTYH and other BER glycosylases [13]. In this review, we will highlight recent insights into the structural and functional properties of MutY, MUTYH and MAP variants. For example, recent investigations of MAP variants in the David laboratory resulted in the discovery of a second metal binding site in mammalian homologs of MUTYH [14]. Furthermore, despite MutY's discovery almost 30 years ago, new features of MutY base excision have been revealed prompting revisions to the accepted mechanism for MutY, implicating that similar revisions may be appropriate for related glycosylases [15]. We also look beyond MAP and call attention to MUTYH's roles in other diseases, including intriguing links between MUTYH and neurological disorders [16], [17], [18], [19]. These various aspects of MUTYH collectively accentuate how the structure and function of MutY and MUTYH elegantly tie to their activities in the cell and the ever-unraveling roles they play in protecting life from DNA damage. Of note, in this review, we highlight primarily new studies and therefore direct the reader to previous reviews on MutY, MUTYH and MAP for additional details [12], [20], [21], [22], [23], [24], [25], [26], [27].
    Oxidatively damaged DNA and base excision repair
    The MutY mechanism in depth DNA repair glycosylases are responsible for recognizing specific types of DNA damage and performing subsequent base excision catalysis, and must function appropriately to complete repair and maintain genomic integrity [4]. The necessary role of MUTYH in preventing mutations and associated diseases has been well established, and much information has been provided on the details of how MutY enzymes recognize 8-oxoG:A mismatches and catalyze base excision [12]. However, new insights into the activity of MutY enzymes continue to be discovered. Detailing the chemistry of MutY's “search and rescue” mission will help researchers gain understanding of the etiology of MAP, as well as determine the relative cellular impacts of different variants. Detailed knowledge of the mechanism of enzymes similar to DNA glycosylases has previously led to development of small molecule inhibitors, paving the way for the design of new pharmaceutical drugs [66]. Furthermore, the idea of targeting DNA repair enzymes as a therapeutic strategy is gaining ground within the cancer research community [13], [67], [68].