Microsatellite repeat instability and neurological disease

Brouwer, J.T.; Willemsen, Rob; Oostra, Ben A.

doi:10.1002/bies.080122

Cited by 125 publications

(126 citation statements)

References 108 publications

(183 reference statements)

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“…In addition to clarifying the nature of MutLα activation, the findings described here may have implications for the expansion of ðCAGÞ n ∶ðCTGÞ n triplet repeat sequences, the cause of a number of neurodegenerative diseases (30,31). Somatic expansion, which depends on both MutSβ and MutLα has been attributed to processing of strand slippage products, with the probability of such slippage events increasing with repeat number (31,32).…”

Section: Discussionmentioning

confidence: 74%

PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair

Pluciennik¹,

Dzantiev²,

Iyer³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

239

294

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MutLα (MLH1-PMS2) is a latent endonuclease that is activated in a mismatch-, MutSα-, proliferating cell nuclear antigen (PCNA)-, replication factor C (RFC)-, and ATP-dependent manner, with nuclease action directed to the heteroduplex strand that contains a preexisting break. RFC depletion experiments and use of linear DNAs indicate that RFC function in endonuclease activation is limited to PCNA loading. Whereas nicked circular heteroduplex DNA is a good substrate for PCNA loading and for endonuclease activation on the incised strand, covalently closed, relaxed circular DNA is a poor substrate for both reactions. However, covalently closed supercoiled or bubble-containing relaxed heteroduplexes, which do support PCNA loading, also support MutLα activation, but in this case cleavage strand bias is largely abolished. Based on these findings we suggest that PCNA has two roles in MutLα function: The clamp is required for endonuclease activation, an effect that apparently involves interaction of the two proteins, and by virtue of its loading orientation, PCNA determines the strand direction of MutLα incision. These results also provide a potential mechanism for activation of mismatch repair on nonreplicating DNA, an effect that may have implications for the somatic phase of triplet repeat expansion.MutLalpha | genetic instability | cancer | triplet repeats

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Section: Discussionmentioning

confidence: 74%

PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair

Pluciennik¹,

Dzantiev²,

Iyer³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

239

294

View full text Add to dashboard Cite

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“…Although ðCAÞ 4 loops and CAG hairpins both harbor three-way junctions, MSH2/ MSH3 interacts with them distinctly (24,26). Why one template is repaired better than the other is not known, but the consequence is remarkable: Inefficient repair of CAG loops results in mutations that underlie more than 20 hereditary neurodegenerative or neuromuscular diseases (30)(31)(32)(33).…”

mentioning

confidence: 99%

Conformational trapping of Mismatch Recognition Complex MSH2/MSH3 on repair-resistant DNA loops

Lang

Coats

Majka

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Insertion and deletion of small heteroduplex loops are common mutations in DNA, but why some loops are prone to mutation and others are efficiently repaired is unknown. Here we report that the mismatch recognition complex, MSH2/MSH3, discriminates between a repair-competent and a repair-resistant loop by sensing the conformational dynamics of their junctions. MSH2/MSH3 binds, bends, and dissociates from repair-competent loops to signal downstream repair. Repair-resistant Cytosine-Adenine-Guanine (CAG) loops adopt a unique DNA junction that traps nucleotide-bound MSH2/MSH3, and inhibits its dissociation from the DNA. We envision that junction dynamics is an active participant and a conformational regulator of repair signaling, and governs whether a loop is removed by MSH2/MSH3 or escapes to become a precursor for mutation.

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“…Expansion or contraction of SSRs generally happens during DNA replication and is frequent on the lagging strand 21,[26][27][28][29] . SSR length mutations may modify genes 21,30,31 and or cause disorders whether repeats are present in exons, introns or un-transcribed regions 23,[32][33][34][35][36][37][38][39][40] . Triplet repeat expansions can also lead to non-ATG (RAN) translation i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Repeats in exons are possibly those that have functional roles 22,23,32,[71][72][73][74] . Repeat expansion in coding regions can alter protein function which can also result in new function 36 . It is perhaps due to these reasons that presence of SSRs in exons compared with introns is low in the present study, which corroborates studies on different genes and genomes 22,28,62,72,75 .…”

Section: Repeats In Exons/intronsmentioning

confidence: 99%

“…Tough repeats may have functional roles, SSRs instability can lead to disorders or interruption in gene functions or disease susceptibility 23,32,34,40 . Even intronic repeat mutation can be one of the causes for disorders 20,36,81,82 or affect promoter activation 40,83 . It remains to be seen whether repeats found in the present study are susceptible for mutations that may alter functions of genes.…”

Section: Repeats In Exons/intronsmentioning

confidence: 99%

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Few Simple Sequence Repeats in Human Hair

2017

JCBSC

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Abstract:Keratin genes are subgroup of intermediate filament (IF) genes. Keratins expressed in hair are called "hair keratins". Comparison of keratin gene sequences and structural organization has been done earlier but no study has been undertaken that compares human hair keratin genes with orthologues in chimp, orangutan, macaque and platypus, with specific references to simple sequence repeats (SSRs) or microsatellites. This study seeks presence of SSRs in human hair keratin genes and compares their positions in orthologue genes. Although the structural organization of keratin genes is largely conserved, as reported in other studies; some human keratin genes show differences in the number of exons and the lengths of exons/introns, when compared with the orthologues. The present study shows few SSRs in human hair keratin genes, where only one repeat is found in exon of Type I keratin gene KRT31, while additional repeats are present in introns. Some repeats are longer in the human genes whereas some indicate reduction in length compared with orthologues. Many repeats are present in regions that are known for intronic variations. This study revisits the comparisons of structural organization of human hair keratin genes and compares them with the orthologues. The SSRs found here could be useful for monitoring variations in human hair keratin genes that may happen due to hypermutable nature of SSRs.

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Microsatellite repeat instability and neurological disease

Cited by 125 publications

References 108 publications

PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair

PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair

Conformational trapping of Mismatch Recognition Complex MSH2/MSH3 on repair-resistant DNA loops

Few Simple Sequence Repeats in Human Hair

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