Related Experiment Video

Updated: Jul 2, 2026

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
09:34

Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease

Published on: April 4, 2018

Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q

Ivana Marinovic-Terzic1, Atsuko Yoshioka-Yamashita, Hideki Shimodaira

  • 1Moores Cancer Center, University of California, San Diego, School of Medicine, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.

Proceedings of the National Academy of Sciences of the United States of America
|September 5, 2008
PubMed

Insights

The postmeiotic segregation 2 (PMS2) protein is crucial for cisplatin chemotherapy effectiveness. A common PMS2 variant (R20Q) impairs this DNA repair pathway, potentially affecting cancer treatment outcomes.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • DNA mismatch repair (MMR) corrects DNA replication errors and triggers apoptosis in response to DNA damage.
  • MMR-deficient cells exhibit resistance to cisplatin chemotherapy due to impaired apoptotic signaling.
  • The MMR protein PMS2 is essential for activating p73-dependent apoptosis following cisplatin treatment.

Purpose of the Study:

  • To investigate the role of PMS2 variants in cisplatin-induced apoptosis.
  • To determine if the PMS2(R20Q) variant affects the apoptotic response to cisplatin.
  • To assess the impact of PMS2 polymorphism on chemotherapy efficacy.

Main Methods:

  • Functional analysis of PMS2 and its variant (R20Q) in Pms2-deficient mouse fibroblasts.
  • Assessment of p73 activation and apoptosis induction in response to cisplatin.
  • Clonogenic survival assays to measure cisplatin cytotoxicity.

Main Results:

  • The PMS2(R20Q) variant was defective in activating p73-dependent apoptosis following cisplatin exposure.
  • Expression of PMS2(R20Q) in Pms2-deficient cells inhibited the apoptotic response to cisplatin.
  • Wild-type PMS2, but not PMS2(R20Q), enhanced the cytotoxic effects of cisplatin.

Conclusions:

  • The PMS2(R20Q) variant lacks proapoptotic activity, disrupting cisplatin-induced DNA damage response.
  • This polymorphic PMS2 allele may influence individual patient responses to cisplatin-based chemotherapy.
  • Understanding PMS2 variants could personalize cancer treatment strategies.

More Related Videos

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila06:41

In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila

Published on: August 20, 2019

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Mismatch Repair01:20

Mismatch Repair

Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
Mismatch Repair01:36

Mismatch Repair

Overview
Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
RNA Splicing01:32

RNA Splicing

Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
Alternative RNA Splicing02:18

Alternative RNA Splicing

Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...