Fig 2: Integrated role of senataxin in meiotic sex chromosome inactivation (MSCI). MSCI is initiated with breast cancer type 1 susceptibility protein (BRCA1) first coating the axial element of the XY chromosomes during the pachytene stage. This is followed by recruitment of senataxin and ataxia telangiectasia and Rad3-related protein (ATR)-interacting partner (ATR/ATRIP) where both senataxin and ATRIP are present as SUMOylated proteins. Binding of TopBP1 activates ATR, which then disperses into the XY chromatin domain where it functions to phosphorylate other proteins, which may include histone H2AX (γH2AX). This step is senataxin-dependent. ATR diffusion into surrounding chromatin is not essential for H2AX phosphorylation as this occurs in the absence of senataxin where ATR is confined to the axial elements of XY chromosomes. Senataxin acts to resolve R-loops on XY chromosomes and associates with CHD4, which is part of the nucleosome remodeling complex (NuRD), to assist in the deacetylation of histones to downregulate active gene expression. The remodeling of chromatin for MSCI is dependent on senataxin. In addition, monomethylation of H3K4 occurs, all of which gives rise to heterochromatin formation and XY silencing.

Fig 3: The Atr-associated checkpoint complex inhibits axon regeneration.a TopBP1/mus101 and Hus1-like mutants, mus101A and Hus1-likeMI11259, and class III da neuron-specific expression of Atrip/mus304 RNAis, Rad17 RNAis, Rad1 RNAis, TopBP1/mus101 RNAi, or Claspin RNAis increase axon regeneration. The injury site is demarcated by the dashed circle. Arrow marks axon stalling while arrowheads show the regrowing axon tips. b The single-stranded DNA-damage pathway mediated by Atr, Chek1, Cdc25, and the associated checkpoint complex. The factors marked by the red cross are tested for their potential role in axon regeneration. c, d Quantifications of class III da neuron axon regeneration with regeneration percentage (c) and regeneration index (d). N = 72, 20, 27, 24, 30, 32, 29, 24, 23, 44, 29, 23, and 37 neurons from 6 to 20 larvae. P = 0.0002, <0.0001, <0.0001, <0.0001, 0.0007, 0.0005, <0.0001, <0.0001, <0.0001, 0.0002, 0.0447. *P < 0.05, **P < 0.01, ***P < 0.001 by two-sided Fisher’s exact test (c), one-way ANOVA followed by Dunn’s test (d), two-tailed unpaired Student’s t-test (d, P = 0.0191). Scale bar = 20 μm. Source data are provided as a Source data file.