eLS: Mismatch Repair Genes

Kansikas M, Nyström M & Peltomäki P.

The mismatch repair (MMR) system is necessary for the maintenance of genomic stability. The primary role of MMR is to correct errors such as base/base mismatches and small insertions/deletions that arise during DNA (deoxyribonucleic acid) synthesis. Loss of functional MMR results in increased rates of point mutations and microsatellite instability. Post-replicative MMR is strand-specific and serves mutation avoidance. Outside replication, discrimination between old and newly synthesised DNA strands is no longer necessary, and the MMR system can be mutagenic. Such non-canonical actions of MMR are required, for example, for the generation of immunoglobulin diversity. The anti-mutator and mutator activities of MMR play important roles in human diseases. Notably, germline mutations in MMR genes cause predisposition to Lynch syndrome, whereas epigenetic inactivation of the MMR gene MLH1 underlies 15% of sporadic colorectal and other cancers.

 

Link to updated article. eLS, 2017.

 

Pathogenic pseudoexons in APC mutation-negative FAP

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis

Nieminen TT, Pavicic W, Porkka N, Kankainen M, Järvinen HJ, Lepistö A, Peltomäki P.

Allele-specific expression (ASE) of the Adenomatous Polyposis Coli (APC) gene occurs in up to one-third of families with adenomatous polyposis (FAP) that have screened mutation-negative by conventional techniques. To advance our understanding of the genomic basis of this phenomenon, 54 APC mutation-negative families (21 with classical FAP and 33 with attenuated FAP, AFAP) were investigated. We focused on four families with validated ASE and scrutinized these families by sequencing of the blood transcriptomes (RNA-seq) and genomes (WGS). Three families, two with classical FAP and one with AFAP, revealed deep intronic mutations associated with pseudoexons. In all three families, intronic mutations (c.646-1806T>G in intron 6, c.1408+729A>G in intron 11, and c.1408+731C>T in intron 11) created new splice donor sites resulting in the insertion of intronic sequences (of 127 bp, 83 bp, and 83 bp, respectively) in the APC transcript. The respective intronic mutations were absent in the remaining polyposis families and the general population. Premature stop of translation as the predicted consequence as well as co-segregation with polyposis supported the pathogenicity of the pseudoexons. We conclude that next generation sequencing on RNA and genomic DNA is an effective strategy to reveal and validate pseudoexons that are regularly missed by traditional screening methods and is worth considering in apparent mutation-negative polyposis families.

Oncotarget, 2016

Jane and Aatos Erkko Foundation Awards 1.25 million for Hereditary Cancer Research

Prof. Päivi Peltomäki (PI) together with Prof. Minna Nyström (Co-PI) and Prof. Jukka-Pekka Mecklin (Co-PI) were nominated by Jane and Aatos Erkko Foundation to receive a grant of 1.25 million euro for their joint interdisciplinary research to recognize molecular mechanisms of hereditary cancer susceptibility in association with lifestyle and diet in aim to improve diagnosis and cancer prevention.

Announcement in Finnish:

Perinnöllinen syöpä (Lynchin oireyhtymä) syövänkehityksen ja -ehkäisyn mallina

Jane ja Aatos Erkon Säätiö on myöntänyt merkittävän (1.25 miljoonan euron) apurahan professorien Päivi Peltomäen, Minna Nyströmin ja Jukka-Pekka Mecklinin johtamalle poikkitieteelliselle hankkeelle.

Syövän synty nähdään pääsääntöisesti joko elintavoista tai synnynnäisestä alttiudesta johtuvaksi. Elintapatekijöiden vaikutusta on edelleenkin vaikea tutkimuksellisesti konkretisoida. Tuoreet tutkimuslöydöksemme kuitenkin paljastivat, että elintapatekijät kuten ravinto ja liikunta näyttävät vaikuttavan myös perinnöllisen syövän syntyyn. Tässä tutkimuksessa pyritään yhdistämään eri lähestymistapoja ja käyttämään pitkään tunnettua periytyvää suolisyöpäalttiutta syövän syntymekanismien ja ehkäisyn mallina ja vertaamaan havaintoja niihin suolisyöpiin, joiden ajatellaan syntyvän ei-periytyvästi.

Tutkimusprojekti selvittää, miksi alttius sairastua paksusuolisyöpään vaihtelee yksilöllisesti, mitkä ovat kasvaimen molekyyli- ja kudostason syntymekanismit ja miten kehittyminen syöväksi voidaan estää. Tieteellisten tavoitteiden ohella tutkimuksella on tärkeä kansanterveydellinen päämäärä: tehostaa paksusuolisyövän ehkäisyä alttiuden varhaisen tunnistamisen ja omien elintapavalintojen kautta.

Erkko2016

Nobel Lecture 2015 on DNA repair

Professor Nyström has the honour of delivering the Nobel Lecture 2015 in recognition of Professor Lindahl, Modrich and Sancar and their Chemistry 2015 Nobel prize winning work “For mechanistic studies of DNA repair”.

The lecture will be held together with Professor Meri’s lecture on the Physiology or Medicine Nobel prize winners works.

The lectures will be delivered on Wednesday, October 21st, 11.00-12.00 in Biocenter 2, Lecture hall 2041.

Visit of Vice-President of the European Comission

Kristalina Georgieva, Vice-President of the European Comission visited the laboratory of Päivi Peltomäki at the Department of Medical and Clinical Genetics in February. Prof. Päivi Peltomäki together with Prof. Minna Nyström presented the projects funded by the European Research Council (ERC) during years 2009-2014. After the meeting Kristalina Georgieva took time to tour around the laboratory!

Read more about the visit at the European Comission website.

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