Related Experiment Video

Updated: Jan 8, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

597

Oncometabolite fumarate impairs ATR-CHK1 signaling by succinating RPA1 in Fumarate Hydratase-deficient renal cell

Nian Liu1, Changxian Shen1,2, Tingting Zhou1

  • 1Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, California, CA91010, USA.

Biorxiv : the Preprint Server for Biology
|December 22, 2025
PubMed

Insights

High fumarate levels in FH-dRCC impair DNA repair by modifying RPA1 protein. This succination disrupts ATR-CHK1 signaling, leading to genomic instability and promoting cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) is characterized by abnormal fumarate accumulation.
  • The precise mechanisms linking fumarate accumulation to FH-dRCC pathogenesis are not fully understood.

Purpose of the Study:

  • To investigate how elevated fumarate levels impact DNA damage response pathways in FH-dRCC.
  • To elucidate the molecular mechanisms underlying fumarate-induced cellular dysfunction.

Main Methods:

  • Analysis of ATR-CHK1 signaling activation under replication stress.
  • Identification of fumarate modifications on RPA1 using mass spectrometry.
  • Assessment of RPA1 binding to single-stranded DNA (ssDNA).
  • Evaluation of DNA repair and cell cycle arrest in response to DNA damage.

Main Results:

  • High fumarate levels inhibit ATR-CHK1 signaling activation.
  • Fumarate modifies RPA1 via succination, primarily at cysteine residues 481 and 486.
  • Succination reduces RPA1's affinity for ssDNA, impairing TOPBP1 recruitment and CHK1 activation.
  • Succinated RPA1 compromises homologous recombination repair and cell cycle control, increasing genomic instability.

Conclusions:

  • Fumarate-induced succination of RPA1 is a novel mechanism contributing to genomic instability in FH-dRCC.
  • This modification impairs DNA repair and cell cycle regulation, highlighting a key role for oncometabolites in cancer development.
Keywords:
ATR-CHK1 pathwayFumarate hydratase-deficient renal cell carcinoma (FHdRCC)Replication Protein A1 (RPA1)Succinationgenome instability

More Related Videos

Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors04:36

Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors

Published on: October 17, 2025

803
Author Spotlight: Exploring the Role of FAM83A in Cervical Cancer04:20

Author Spotlight: Exploring the Role of FAM83A in Cervical Cancer

Published on: February 9, 2024

1.4K

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.6K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.6K
Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
18.3K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
5.2K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
7.8K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.1K