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  • neurokinin 1 receptor br MUTYH associated polyposis br MUTYH

    2021-10-23


    MUTYH-associated polyposis
    MUTYH and its metal cofactors MUTYH harbors two vital cofactors, both of which are located remotely from the active site (Fig. 6). One of these cofactors, a [4Fe-4S]2+(Fe-S) cluster, is chelated by four Cys residues in the N-terminal domain, and positions an Fe-S cluster loop (FCL) motif that mediates interactions with the DNA substrate [69]. All but a few recently identified homolog lineages of MutY possess this iron-sulfur cluster [149]. The second cofactor is a recently identified Zn2+ ion, coordinated to three Cys residues in the interdomain connector (IDC) of higher eukaryotic MutY homologs; this region of MUTYH has been dubbed the “Zn2+ linchpin motif” to embody its structural and functional roles [14]. These two MUTYH cofactors are essential for efficient repair in cells, but their exact role in DNA repair and regulation is still under investigation [14], [134], [150], [151].
    Beyond MAP: other implications of MUTYH in medicine
    Concluding remarks and perspectives The 2015 Nobel Prize in Chemistry was awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar for “having mapped, at the molecular level, how cells repair damaged DNA and safeguard the genetic information” [192]. Indeed, the work of Lindahl and Modrich led to the discovery of MutY, and its unusual activity as an neurokinin 1 receptor glycosylase. These discoveries paved the way for uncovering the important role of MutY and MUTYH in preventing mutations associated with 8-oxoG, and the discovery of MAP. The role of MUTYH variants in MAP underscores the harmful nature of oxidatively damaged DNA, and the importance of mechanisms for maintaining the genome in the face of continued oxidative insults. Despite the large amount of neurokinin 1 receptor work on delineating the structural and functional properties of MutY, new features have recently been unveiled. One of these new discoveries was uncovering the presence of a previously unrecognized Zn2+ ion in the IDC of MUTYH, and demonstrating a critical role for the Zn2+ linchpin motif in damage recognition and repair. This discovery, along with the many new studies of Fe-S clusters in BER glycosylases, and other DNA repair enzymes, prompt additional work on determining how these metal sites may be utilized during MUTYH-mediated DNA damage response, and the potential impact of MAP variants on metal cofactor function. In addition, the discovery that MutY is a retaining glycosidase prompts additional studies to further define this mechanism, and to determine if similar mechanisms are operative in other BER glycosylases. Moreover, these mechanistic features may be exploited to design new therapeutic strategies to target MUTYH. Lastly, the details by which MutY finds 8-oxoG:A mismatches is still unclear, and the exact defects of many MAP variants are also a mystery. We envision that structural, biophysical and mechanistic studies of MUTYH and MAP variants will be even more needed going forward. Lastly, we anticipate that new discoveries of the role of MUTYH in human disease will come from many directions, such as those capitalizing on new advances in DNA sequencing, as well as probing gene functions in cells with new gene editing tools.
    Acknowledgements We are particularly grateful for the wonderful cadre of people that have passed through the David laboratory, and have helped in building our part of the MutY/MUTYH story piece by piece. We especially thank Drs. Jeremy Cheadle and Julian Sampson for recruiting us to work with them in the discovery of MAP. We also thank Dr. Martin Horvath for our on-going collaboration that led to the Gs MutY TSAC structure. Our work on the topics of this review was funded by the National Cancer Institute (CA067985). Doug Banda and Katie Bradshaw were supported by a National Institute of Environmental Health Sciences funded training program in Environmental Health Sciences (T32 ES007058). We apologize for not citing all of the work on MutY and MUTYH due to limitations on space and time.