Nonamer dependent RAG cleavage at CpGs can explain mechanism of chromosomal translocations associated to lymphoid cancers.
Chromosomal translocations are considered as one of the major causes of lymphoid cancers. RAG complex, which is responsible for V(D)J recombination, can also cleave non-B DNA structures and cryptic RSSs in the genome leading to chromosomal translocations. The mechanism and factors regulating the ill...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-10-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010421 |
| _version_ | 1811244203350425600 |
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| author | Amita M Paranjape Sagar S Desai Mayilaadumveettil Nishana Urbi Roy Namrata M Nilavar Amrita Mondal Rupa Kumari Gudapureddy Radha Vijeth Kumar Katapadi Bibha Choudhary Sathees C Raghavan |
| author_facet | Amita M Paranjape Sagar S Desai Mayilaadumveettil Nishana Urbi Roy Namrata M Nilavar Amrita Mondal Rupa Kumari Gudapureddy Radha Vijeth Kumar Katapadi Bibha Choudhary Sathees C Raghavan |
| author_sort | Amita M Paranjape |
| collection | DOAJ |
| description | Chromosomal translocations are considered as one of the major causes of lymphoid cancers. RAG complex, which is responsible for V(D)J recombination, can also cleave non-B DNA structures and cryptic RSSs in the genome leading to chromosomal translocations. The mechanism and factors regulating the illegitimate function of RAGs resulting in oncogenesis are largely unknown. Upon in silico analysis of 3760 chromosomal translocations from lymphoid cancer patients, we find that 93% of the translocation breakpoints possess adjacent cryptic nonamers (RAG binding sequences), of which 77% had CpGs in proximity. As a proof of principle, we show that RAGs can efficiently bind to cryptic nonamers present at multiple fragile regions and cleave at adjacent mismatches generated to mimic the deamination of CpGs. ChIP studies reveal that RAGs can indeed recognize these fragile sites on a chromatin context inside the cell. Finally, we show that AID, the cytidine deaminase, plays a significant role during the generation of mismatches at CpGs and reconstitute the process of RAG-dependent generation of DNA breaks both in vitro and inside the cells. Thus, we propose a novel mechanism for generation of chromosomal translocation, where RAGs bind to the cryptic nonamer sequences and direct cleavage at adjacent mismatch generated due to deamination of meCpGs or cytosines. |
| first_indexed | 2024-04-12T14:21:52Z |
| format | Article |
| id | doaj.art-54f57c96c51f4ad5b0b272d0cb05032a |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-12T14:21:52Z |
| publishDate | 2022-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-54f57c96c51f4ad5b0b272d0cb05032a2022-12-22T03:29:33ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042022-10-011810e101042110.1371/journal.pgen.1010421Nonamer dependent RAG cleavage at CpGs can explain mechanism of chromosomal translocations associated to lymphoid cancers.Amita M ParanjapeSagar S DesaiMayilaadumveettil NishanaUrbi RoyNamrata M NilavarAmrita MondalRupa KumariGudapureddy RadhaVijeth Kumar KatapadiBibha ChoudharySathees C RaghavanChromosomal translocations are considered as one of the major causes of lymphoid cancers. RAG complex, which is responsible for V(D)J recombination, can also cleave non-B DNA structures and cryptic RSSs in the genome leading to chromosomal translocations. The mechanism and factors regulating the illegitimate function of RAGs resulting in oncogenesis are largely unknown. Upon in silico analysis of 3760 chromosomal translocations from lymphoid cancer patients, we find that 93% of the translocation breakpoints possess adjacent cryptic nonamers (RAG binding sequences), of which 77% had CpGs in proximity. As a proof of principle, we show that RAGs can efficiently bind to cryptic nonamers present at multiple fragile regions and cleave at adjacent mismatches generated to mimic the deamination of CpGs. ChIP studies reveal that RAGs can indeed recognize these fragile sites on a chromatin context inside the cell. Finally, we show that AID, the cytidine deaminase, plays a significant role during the generation of mismatches at CpGs and reconstitute the process of RAG-dependent generation of DNA breaks both in vitro and inside the cells. Thus, we propose a novel mechanism for generation of chromosomal translocation, where RAGs bind to the cryptic nonamer sequences and direct cleavage at adjacent mismatch generated due to deamination of meCpGs or cytosines.https://doi.org/10.1371/journal.pgen.1010421 |
| spellingShingle | Amita M Paranjape Sagar S Desai Mayilaadumveettil Nishana Urbi Roy Namrata M Nilavar Amrita Mondal Rupa Kumari Gudapureddy Radha Vijeth Kumar Katapadi Bibha Choudhary Sathees C Raghavan Nonamer dependent RAG cleavage at CpGs can explain mechanism of chromosomal translocations associated to lymphoid cancers. PLoS Genetics |
| title | Nonamer dependent RAG cleavage at CpGs can explain mechanism of chromosomal translocations associated to lymphoid cancers. |
| title_full | Nonamer dependent RAG cleavage at CpGs can explain mechanism of chromosomal translocations associated to lymphoid cancers. |
| title_fullStr | Nonamer dependent RAG cleavage at CpGs can explain mechanism of chromosomal translocations associated to lymphoid cancers. |
| title_full_unstemmed | Nonamer dependent RAG cleavage at CpGs can explain mechanism of chromosomal translocations associated to lymphoid cancers. |
| title_short | Nonamer dependent RAG cleavage at CpGs can explain mechanism of chromosomal translocations associated to lymphoid cancers. |
| title_sort | nonamer dependent rag cleavage at cpgs can explain mechanism of chromosomal translocations associated to lymphoid cancers |
| url | https://doi.org/10.1371/journal.pgen.1010421 |
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