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Regulation of DIM-2-dependent repeat-induced point mutation (RIP) by the recombination-independent homologous DNA pairing in Neurospora crassa

Florian Carlier, Tinh-Suong Nguyen, Alexey K. Mazur, View ORCID ProfileEugene Gladyshev
doi: https://doi.org/10.1101/2021.04.05.438447
Florian Carlier
1Group “Fungal Epigenomics”, Department of Mycology, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France
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Tinh-Suong Nguyen
1Group “Fungal Epigenomics”, Department of Mycology, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France
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Alexey K. Mazur
1Group “Fungal Epigenomics”, Department of Mycology, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France
2CNRS, Université de Paris, UPR 9080, Laboratoire de Biochimie Théorique, 13 rue Pierre et Marie Curie, F-75005, Paris, France
3Institut de Biologie Physico-Chimique-Fondation Edmond de Rothschild, PSL Research University, Paris, France
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  • For correspondence: alexey@ibpc.fr eugene.gladyshev@gmail.com
Eugene Gladyshev
1Group “Fungal Epigenomics”, Department of Mycology, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris, France
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  • ORCID record for Eugene Gladyshev
  • For correspondence: alexey@ibpc.fr eugene.gladyshev@gmail.com
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ABSTRACT

Repeat-induced point mutation (RIP) is a genetic process that creates cytosine-to-thymine (C-to-T) transitions in duplicated genomic sequences in fungi. RIP detects duplications irrespective of their origin, particular sequence, coding capacity, or genomic positions. Previous studies suggested that RIP involves a cardinally new mechanism of sequence recognition that operates on intact double-stranded DNAs. In the fungus Neurospora crassa, RIP can be mediated by a putative C5-cytosine methyltransferase (CMT) RID or/and a canonical CMT DIM-2. These distinct RIP pathways feature opposite substrate preferences: RID-dependent RIP is largely limited to the duplicated sequences, whereas DIM-2-dependent RIP preferentially mutates adjacent non-repetitive regions. Using DIM-2-dependent RIP as a principal readout of repeat recognition, here we show that GC-rich repeats promote stronger RIP compared to AT-rich repeats (independently of their intrinsic propensities to become mutated), with the relative contribution of AT base-pairs being close to zero. We also show that direct repeats promote much more efficient DIM-2-dependent RIP than inverted repeats; both the spacer DNA between the repeat units (the linker) and the flanking regions are similarly affected by this process. These and other results support the idea that repeat recognition for RIP involves formation of many short interspersed quadruplexes between homologous double-stranded DNAs, which need to undergo concomitant changes in their linking number to accommodate pairing.

SUMMARY During repeat-induced point mutation (RIP) gene-sized duplications of genomic DNA are detected by a mechanism that likely involves direct pairing of homologous double-stranded DNAs. We show that DIM-2-dependent RIP, triggered by closely-positioned duplications, is strongly affected by their relative orientations (direct versus inverted). We also show that GC-rich repeats promote RIP more effectively than AT-rich repeats. These results support a model in which homologous dsDNAs can pair by establishing interspersed quadruplex-based contacts with concomitant changes in their supercoiling status.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 06, 2021.
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Regulation of DIM-2-dependent repeat-induced point mutation (RIP) by the recombination-independent homologous DNA pairing in Neurospora crassa
Florian Carlier, Tinh-Suong Nguyen, Alexey K. Mazur, Eugene Gladyshev
bioRxiv 2021.04.05.438447; doi: https://doi.org/10.1101/2021.04.05.438447
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Regulation of DIM-2-dependent repeat-induced point mutation (RIP) by the recombination-independent homologous DNA pairing in Neurospora crassa
Florian Carlier, Tinh-Suong Nguyen, Alexey K. Mazur, Eugene Gladyshev
bioRxiv 2021.04.05.438447; doi: https://doi.org/10.1101/2021.04.05.438447

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