Amber Rudd has quit the cabinet and as a Conservative Party member over Boris Johnson's approach to Brexit.
The work and pensions secretary accused the prime minister of "an assault on decency and democracy" over the sacking of 21 Tory MPs who backed moves to prevent the UK leaving the EU without a deal.
Rudd said Johnson was guilty of "political vandalism" and claimed No.10 was now pursuing no-deal as official government policy.
And she vowed to "play whatever role I can" to return UK politics to the centre ground.
In response, Downing Street hit out at "resignations to chase headlines" and insisted the government would not be shaken in its determination to deliver Brexit and then focus on domestic issues.
Rudd has been replaced at the Department for Work and Pensions by Thérèse Coffey, who has been promoted from the Department for Environment, Food and Rural Affairs, where she was environment and rural opportunity minister.
Rudd's resignation comes just six weeks after she agreed to serve in Johnson's cabinet, despite the pair's well-documented differences over Brexit.
In her letter to the PM, she said: "I joined your cabinet in good faith: accepting that no deal had to be on the table, because it was the means by which we would have the best chance of achieving a new deal to leave on 31 October.
"However I no longer believe leaving with a deal is the government's main objective."
The Hastings MP, once tipped as a future Conservative Party leader, went on: "I must also address the assault on decency and democracy that took place last week when you sacked 21 talented, loyal One Nation Conservatives.
"The short-sighted culling of my colleagues has stripped the party of broad-minded and dedicated Conservative MPs. I cannot support this act of political vandalism.
"Therefore, it is with regret that I am also surrendering the Conservative whip. Britain's body politic is under attack from both sides of the ideological debate. I will no play whatever role I can to help return it to a better place."
A Downing Street spokesman said: "We are disappointed to learn that Amber has chosen to leave government and the party. She was a talented welfare minister but all ministers who joined Cabinet signed up to leaving the EU on 31 October come what may, delivering on the referendum result as the public were promised. That has not changed."
A senior government source added: "As the polls show, the public do not back attempts by some MPs to cancel the referendum. Resignations to chase headlines won’t change the fact that people want Brexit done so that government can deliver on the domestic priorities people care about like more police, new hospitals and great schools."
It is understood that the prime minister first learned of Ms Rudd's intention to quit from the media, and that calls to the MP throughout Saturday went unanswered.
But a source close to Rudd told CSW's sister title PoliticsHome: "They spoke this evening for 10 minutes on the phone. He asked her to reconsider but her mind was made up.
"She supported his no deal pledge, but the sackings were too much."
Meanwhile, a source close to the sacked MPs said: "The wheels are coming off the Dominic Cummings' Downing Street machine.
"The sham negotiation has been exposed for what it is – and he has no Plan B. He’s single-handedly trying to turn the Conservative party into an extreme right-wing faction – and moderates are clearly not welcome."