Multifaceted roles of SUMO in DNA metabolism.

Sumoylation, a process in which SUMO (small ubiquitin like modifier) is conjugated to target proteins, emerges as a post-translational modification that mediates protein-protein interactions, protein complex assembly, and localization of target proteins. The coordinated actions of SUMO ligases, proteases, and SUMO-targeted ubiquitin ligases determine the net result of sumoylation. It is well established that sumoylation can somewhat promiscuously target proteins in groups as well as selectively target individual proteins.

rescues the mild methylmethane sulfonate sensitivity of Δ cells in .

Sgs1p in belongs to the RecQ helicase family. Sgs1p is involved in recombination during DNA damage repair and sumoylation of Sgs1p is one mechanism by which the protein is regulated. To further understand the significance of Sgs1p sumoylation in DNA damage repair, we examined the genetic interaction between SUMO mutants and a mutant of , the protein product of which also prevents aberrant recombination structures.

Students' Perceptions of FSBio 201, A CURE-Based Course that Scaffolds Research and Scientific Communication, Align with Learning Outcomes.

Incorporating active research opportunities into undergraduate curricula is one of the most cited elements demonstrated to improve inclusive excellence and retention in all STEM fields. Allegheny College has a long and nationally-recognized tradition of collaborative student-faculty research within the academic curriculum and as co-curricular opportunities. We present an example of the former, a Course-based Undergraduate Research Experience (CURE), FSBio 201, that has been central to Allegheny's biology curriculum for over two decades.

How Not To Be in the Wrong Place at the Wrong Time: An Education Primer for Use with "Deposition of Centromeric Histone H3 Variant CENP-A/Cse4 into Chromatin Is Facilitated by Its C-Terminal Sumoylation".

Recent work by Kentaro Ohkuni and colleagues exemplifies how a series of molecular mechanisms contribute to a cellular outcome-equal distribution of chromosomes. Failure to maintain structural and numerical integrity of chromosomes is one contributing factor in genetic diseases such as cancer. Specifically, the authors investigated molecular events surrounding centromeric histone H3 variant Cse4 deposition-a process important for chromosome segregation, using as a model organism.

Flap endonuclease overexpression drives genome instability and DNA damage hypersensitivity in a PCNA-dependent manner.

Overexpression of the flap endonuclease FEN1 has been observed in a variety of cancer types and is a marker for poor prognosis. To better understand the cellular consequences of FEN1 overexpression we utilized a model of its Saccharomyces cerevisiae homolog, RAD27. In this system, we discovered that flap endonuclease overexpression impedes replication fork progression and leads to an accumulation of cells in mid-S phase.

Slx5/Slx8 Promotes Replication Stress Tolerance by Facilitating Mitotic Progression.

Loss of minichromosome maintenance protein 10 (Mcm10) causes replication stress. We uncovered that S. cerevisiae mcm10-1 mutants rely on the E3 SUMO ligase Mms21 and the SUMO-targeted ubiquitin ligase complex Slx5/8 for survival.

MCM10: one tool for all-Integrity, maintenance and damage control.

Minichromsome maintenance protein 10 (Mcm10) is an essential replication factor that is required for the activation of the Cdc45:Mcm2-7:GINS helicase. Mcm10's ability to bind both ds and ssDNA appears vital for this function. In addition, Mcm10 interacts with multiple players at the replication fork, including DNA polymerase-α and proliferating cell nuclear antigen with which it cooperates during DNA elongation.

Unligated Okazaki Fragments Induce PCNA Ubiquitination and a Requirement for Rad59-Dependent Replication Fork Progression.

Deficiency in DNA ligase I, encoded by CDC9 in budding yeast, leads to the accumulation of unligated Okazaki fragments and triggers PCNA ubiquitination at a non-canonical lysine residue. This signal is crucial to activate the S phase checkpoint, which promotes cell cycle delay. We report here that a pol30-K107 mutation alleviated cell cycle delay in cdc9 mutants, consistent with the idea that the modification of PCNA at K107 affects the rate of DNA synthesis at replication forks.

Enigmatic roles of Mcm10 in DNA replication.

Minichromosome maintenance protein 10 (Mcm10) is required for DNA replication in all eukaryotes. Although the exact contribution of Mcm10 to genome replication remains heavily debated, early reports suggested that it promotes DNA unwinding and origin firing. These ideas have been solidified by recent studies that propose a role for Mcm10 in helicase activation.

Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-κB impairs this drug-induced senescence.

Oncogene-induced senescence can provide a protective mechanism against tumour progression. However, production of cytokines and growth factors by senescent cells may contribute to tumour development. Thus, it is unclear whether induction of senescence represents a viable therapeutic approach.

NF-κB inducing kinase: a key regulator in the immune system and in cancer.

NF-κB inducing kinase (NIK) is a kinase that activates the canonical and non-canonical NF-κB pathways to control transcriptional expression of certain proteins such as cytokines, chemokines and NF-κB signaling molecules. Many advances have been made in understanding the molecular mechanisms by which the stability of NIK is regulated to affect downstream signaling. Genetic mouse models suggest that NIK plays an essential role in the regulation of the immune system as well as in the bone microenvironment.

Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy.

The BRAFV600E mutation is common in human melanoma. This mutation enhances IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) and extracellular signal-regulated kinase/activator protein signaling cascades. In this study, we evaluated the efficacy of targeting either B-Raf or IKKbeta in combination with the DNA alkylating agent temozolomide for treatment of advanced metastatic melanoma.

The lymphotoxin-beta receptor is an upstream activator of NF-kappaB-mediated transcription in melanoma cells.

The pleiotropic transcription factor nuclear factor-kappaB (NF-kappaB (p50/p65)) regulates the transcription of genes involved in the modulation of cell proliferation, apoptosis, and oncogenesis. Furthermore, a host of solid and hematopoietic tumor types exhibit constitutive activation of NF-kappaB (Basseres, D. S.

Role of chemokines in tumor growth.

Chemokines play a paramount role in the tumor progression. Chronic inflammation promotes tumor formation. Both tumor cells and stromal cells elaborate chemokines and cytokines.