Human <scp>DNA</scp> polymerase α interacts with mismatch repair proteins <scp>MSH</scp>2 and <scp>MSH</scp>6

Itkonen, Harri M.; Kantelinen, Jukka; Vaara, Markku; Parkkinen, Sinikka; Schlott, Bernhard; Grosse, Frank; Nyström, Minna; Syväoja, Juhani E.; Pospiech, Helmut

doi:10.1002/1873-3468.12475

Cited by 7 publications

(5 citation statements)

References 39 publications

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“…12,13 It recognizes and corrects mismatched bases that happen due to errors by DNA polymerases as they synthesize short repeats termed microsatellites. [14][15][16] The number of repeats for any microsatellite is constant in a healthy individual but polymorphic across populations. 11 The defects in the repair of short mismatches result in changes in the number of these repetitive sequences in tumor as compared to normal autologous DNA.…”

Section: Introductionmentioning

confidence: 99%

Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma

et al. 2017

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Postreplicative mismatch repair safeguards the stability of our genome. The defects in its functioning will give rise to microsatellite instability. In this study, 50 meningiomas were investigated for microsatellite instability. Two major mismatch repair genes, MLH1 and MSH2, were analyzed using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high-resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability. Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA. Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ = 9.14; p = 0.01). Our study contributes to better understanding of the genetic profile of human intracranial meningiomas and suggests that meningiomas harbor defective cellular DNA mismatch repair mechanisms.

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Section: Introductionmentioning

confidence: 99%

Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma

et al. 2017

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“…A specialized type of MMR that uses FEN1 as exonuclease, without requiring Exonuclease-1 (Exo1), called α-segment error editing (AEE) 72 , has been shown to correct mismatches arising within <12 nt from the 5′ end of α-segments. Polα interacts directly with MutSα 77 , the complex responsible for mismatch and 1–2-nt indel recognition in MMR 78 , which open the possibility that error sites in the α-segments might be prebound by MutSα before the arrival of the NT complex. In AEE, FEN1 and MutSα form a unique complex that dramatically stimulates FEN1 exonuclease activity post-RNA-removal on mismatch-containing α-segments 72 .…”

Section: Discussionmentioning

confidence: 99%

Mechanistic investigation of human maturation of Okazaki fragments reveals slow kinetics

et al. 2022

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The final steps of lagging strand synthesis induce maturation of Okazaki fragments via removal of the RNA primers and ligation. Iterative cycles between Polymerase δ (Polδ) and Flap endonuclease-1 (FEN1) remove the primer, with an intermediary nick structure generated for each cycle. Here, we show that human Polδ is inefficient in releasing the nick product from FEN1, resulting in non-processive and remarkably slow RNA removal. Ligase 1 (Lig1) can release the nick from FEN1 and actively drive the reaction toward ligation. These mechanisms are coordinated by PCNA, which encircles DNA, and dynamically recruits Polδ, FEN1, and Lig1 to compete for their substrates. Our findings call for investigating additional pathways that may accelerate RNA removal in human cells, such as RNA pre-removal by RNase Hs, which, as demonstrated herein, enhances the maturation rate ~10-fold. They also suggest that FEN1 may attenuate the various activities of Polδ during DNA repair and recombination.

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“…MMR is a bacterial MUTS homologue and mainly forms a mismatch complex with MSH2 (MSH2-MSH6) to play a role in mismatch repair. 38 , 39 …”

Section: Discussionmentioning

confidence: 99%

Genetic Alteration and Their Significance on Clinical Events in Small Cell Lung Cancer

Jiao

Zhang

Wang

et al. 2022

CMAR

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Introduction Small cell lung cancer (SCLC), an aggressive subtype of lung cancer characterized by the development of neuroendocrine tumors, is prone to distant metastasis, resistant to platinum-based drugs and has a poor prognosis. The development of next-generation sequencing technology (NGS) has led to the identification of many genetic alterations in SCLC. Few druggable targeted molecules can be used in clinical practice. Currently, NGS is widely employed in routine clinical practice of non-small cell lung cancer to assist in therapeutic options and prognosis evaluation. This study aims to investigate genes involved in small cell lung cancer (SCLC), their occurrence and their significance in clinical events. Methods Tumor tissue specimens from 18 Chinese SCLC patients were collected through a 520 cancer‐related genes panel for next-generation sequencing. First, the association between sequence results and clinical outcomes was examined. Subsequently, data on clinical pathology and sequencing results were analyzed. Results The Kaplan–Meier curve displayed a significant reduction in PFS for SCLC patients with LRP1B or MAP3K13 mutations. Overall survival (OS) of SCLC patients with MSH6 mutation was significantly higher than those with SPEN mutation. Conclusion Next-generation sequencing demonstrates that the genetic landscape of SCLC. Mutation status of LRP1B, MAP3K13, MSH6 and SPEN has prognostic significance, which might be potential therapeutic targets. We found possible genes and related signaling pathways that affect metastasis. These results can improve our understanding of the mutation characteristics of SCLC and identify potential biomarkers to guide targeted therapies.

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Human DNA polymerase α interacts with mismatch repair proteins MSH2 and MSH6

Cited by 7 publications

References 39 publications

Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma

Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma

Mechanistic investigation of human maturation of Okazaki fragments reveals slow kinetics

Genetic Alteration and Their Significance on Clinical Events in Small Cell Lung Cancer

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