Phosphopeptide binding by Sld3 links Dbf4-dependent kinase to MCM replicative helicase activation

The initiation of eukaryotic DNA replication requires the assembly of active CMG (Cdc45-MCM-GINS) helicases at replication origins by a set of conserved and essential firing factors. This process is controlled during the cell cycle by cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK), and in response to DNA damage by the checkpoint kinase Rad53/Chk1. Here we show that Sld3, previously shown to be an essential CDK and Rad53 substrate, is recruited to the inactive MCM double hexamer in a DDK-dependent manner. Sld3 binds specifically to DDK-phosphorylated peptides from two MCM subunits (Mcm4, 6) and then recruits Cdc45. MCM mutants that cannot bind Sld3 or Sld3 mutants that cannot bind phospho-MCM or Cdc45 do not support replication. Moreover, phosphomimicking mutants in Mcm4 and Mcm6 bind Sld3 without DDK and facilitate DDK-independent replication. Thus, Sld3 is an essential "reader" of DDK phosphorylation, integrating signals from three distinct protein kinase pathways to coordinate DNA replication during S phase.
Source: EMBO Journal - Category: Molecular Biology Authors: Tags: DNA Replication, Repair & Recombination Articles Source Type: research

Related Links:

AbstractThe aim of this study was to evaluate the photobiomodulation of red and green lights in the repair process of third-degree skin burns in rats through clinicopathological and immunohistochemical parameters. Sixty male Wistar rats were divided into three groups: control (CTRL) (n = 20), red LED (RED) (n = 20), and green LED (GREEN) (n = 20), with subgroups (n = 5) for each time of euthanasia (7, 14, 21, and 28 days). Daily applications in RED (λ630  ± 10 nm, 300 mW) and GREEN groups (λ520  ± ...
Source: Lasers in Medical Science - Category: Laser Surgery Source Type: research
Authors: Luo J, Zhang S, Tan M, Li J, Xu H, Tan Y, Huang Y Abstract Colorectal cancer (CRC) is a major contributor to cancer-associated mortality in China and remains a vast challenge worldwide. Although the genetic basis of CRC has been investigated, the uncommonly mutated genes in CRC remain unknown, in particular in the Asian population. In the present study, targeted region sequencing on 22 CRC and 10 paired non-cancerous tissues was performed to determine the genetic pattern of CRC samples in the Chinese population. Driver genes were detected by three distinct softwares, including MutSigCV, oncodriveFM and iCA...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
Authors: de Azevedo JWV, de Medeiros Fernandes TAA, Fernandes JV, de Azevedo JCV, Lanza DCF, Bezerra CM, Andrade VS, de Araújo JMG, Fernandes JV Abstract Osteosarcoma (OS) is a bone tumor of mesenchymal origin, most frequently occurring during the rapid growth phase of long bones, and usually located in the epiphyseal growth plates of the femur or the tibia. Its most common feature is genome disorganization, aneuploidy with chromosomal alterations, deregulation of tumor suppressor genes and of the cell cycle, and an absence of DNA repair. This suggests the involvement of surveillance failures, DNA repair or ...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
Authors: Banias L, Jung I, Bara T, Fulop Z, Simu P, Simu I, Satala C, Gurzu S Abstract The aim of the present study was to classify colorectal carcinoma (CRC) into molecular subtypes, based on immunohistochemical (IHC) assessments. A total of 112 CRC samples were molecularly classified based on the expression levels of epithelial-mesenchymal transition (EMT)-associated IHC markers. A total of three molecular subtypes were defined: Epithelial, membrane positivity for E-cadherin and β-catenin, negative for vimentin; mesenchymal, E-cadherin-negative, nuclear β-catenin- and vimentin-positive; and hybrid cases...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
Authors: Yin N, Xie T, Zhang H, Chen J, Yu J, Liu F Abstract Isocitrate dehydrogenase 1 (IDH1) is the most frequently mutated gene in World Health Organization grade II-III and secondary glioma. The majority of IDH1 mutation cases involve the substitution from arginine to histidine at codon 132 (IDH1-R132H). Although the oncogenic role of IDH1-R132H has been confirmed, patients with IDH1-R132H brain tumors exhibit a better response to radiotherapy compared with those with wild-type (WT) IDH1. In the present study, the potential mechanism of radiosensitization mediated by IDH1-R132H was investigated by overexpressin...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
Publication date: Available online 23 January 2020Source: The American Journal of SurgeryAuthor(s): Jeremy A. Warren, Michael Love, William S. Cobb, Lucas R. Beffa, Francisco J. Couto, B.H. Hancock, D. Morrow, Joseph A. Ewing, Alfredo M. CarbonellAbstractBackgroundProsthetic mesh infection (PMI) is a challenging complication of ventral hernia repair (VHR). The sparsity of data leaves only experience and judgment to guide surgical decision-making.MethodsRetrospective review of patients diagnosed with PMI. Subsequent abdominal operation (SAO) constitutes any intraabdominal operation occurring after the index hernia repair pr...
Source: The American Journal of Surgery - Category: Surgery Source Type: research
We describe an arthroscopic sign of an unstable medial meniscal tear that is diagnostic. The “crevice sign” is a longitudinal fissure located on the distal medial femoral condyle. In the anterior cruciate ligament–deficient knee, there is increased strain on the medial meniscus. A posterior longitudinal medial meniscal tear can occur at the time of the index injury or with subsequent instability events. During this injury, the knee pivots and the anterior edge of the unstable medial meniscus digs into the articular cartilage of the medial femoral condyle, resulting in a longitudinal split of the distal fe...
Source: Arthroscopy Techniques - Category: Surgery Source Type: research
We describe a technique using a fascia lata autograft to reconstruct the rotator cuff in the setting of a massive cuff tear. This is of particular importance in centers that lack the funding or institutional approval to use acellular dermal allografts that have been popularized to date.
Source: Arthroscopy Techniques - Category: Surgery Source Type: research
We describe the utilization of arthroscopic anatomic glenoid reconstruction using a distal tibial allograft after a failed Latarjet procedure. Preoperative and operative methodology are described with relevant imaging investigations and a detailed intraoperative arthroscopic technique.
Source: Arthroscopy Techniques - Category: Surgery Source Type: research
This article reviews pre and postoperative management and gives special attention to the rotation advancement, Fisher subunit, and Tennison Triangle techniques of repair.
Source: Operative Techniques in Otolaryngology Head and Neck Surgery - Category: ENT & OMF Source Type: research
More News: Gastroschisis Repair | Molecular Biology